Spiro ring compound as hepatitis c virus (hcv) inhibitor and uses thereof

ABSTRACT

A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a U.S. national stage application of the International PatentApplication No. PCT/CN2013/001463, filed Nov. 28, 2013, which claimspriorities to Chinese Patent Application No. 201210495665.5, filed Nov.29, 2012, and No. 201310116312.4, filed Apr. 4, 2013, all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention is in the field of medicine. The invention relatesto compounds for treating Hepatitis C virus (HCV) infection,compositions comprising such compounds, the uses and the methodsthereof. In particular, the invention relates to spiro ring compoundsused as NS5A protein inhibitors. More specially, the invention relatesto compounds which can inhibit the function of the NS5A protein encodedby Hepatitis C virus (HCV), pharmaceutical compositions comprising suchcompounds, and methods for inhibiting the function of the NS5A protein.

BACKGROUND OF THE INVENTION

HCV is a major human pathogen, infecting an estimated 170 millionpersons worldwide roughly five times the number infected by humanimmunodeficiency virus type I. A substantial fraction of these HCVinfected individuals develop serious progressive liver disease,including cirrhosis and hepatocellular carcinoma. Chronic HCV infectionis thus a major worldwide cause of liver-related premature mortality.

Presently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients. Recent clinical results demonstrate that pegylatedalpha-interferon is superior to unmodified alpha-interferon asmonotherapy. However, even with experimental therapeutic regimensinvolving combinations of pegylated alpha-interferon and ribavirin, asubstantial fraction of patients do not have a sustained reduction inviral load. The treatment has side effects in many patients, so they donot durably respond to treatment. Thus, new and effective methods oftreating HCV infection are urgently needed.

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the 5′untranslated region, HCV has been classified as a separate genus in theFlaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame (ORF).

Considerable heterogeneity is found within nucleotide and encoded aminoacid sequence throughout the HCV genome. At least seven major genotypeshave been characterized, and more than 50 subtypes have been described.In HCV infected cells, viral RNA is translated into a polyprotein thatis cleaved into ten individual proteins. At the amino terminus arestructural proteins, follows E1 and E2. Additionally, there are sixnon-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which playa function role in the HCV lifecycle (see, for example, Lindenbach etal., Nature, 2005, 436, 933-938).

The major genotypes of HCV differ in their distribution worldwide, andthe clinical significance of the genetic heterogeneity of HCV remainselusive despite numerous studies of the possible effect of genotypes onpathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A and NS5B) is effected by two viral proteases. The firstone is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease within the N-terminalregion of NS3 (also referred herein as NS3 protease) and mediates allthe subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4Acleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A,NS5A-NS5B sites. The NS4A protein appears to serve multiple functions,acting as a cofactor for the NS3 protease and possibly assisting in themembrane localization of NS3 and other viral replicase components. Thecomplex formation of the NS3 protein with NS4A seems necessary to theprocessing events, enhancing the proteolytic efficiency at all of thesites. The NS3 protein also exhibits nucleoside triphosphatase and RNAhelicase activities. NS5B (also referred to herein as HCV polymerase) isa RNA-dependent RNA polymerase that is involved in the replication ofHCV.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in Tan et al.,Virology. 2001, 284, 1-12; and in Park et al., J. Biol. Chem., 2003,278, 30711-30718.

SUMMARY OF THE INVENTION

Provided herein are novel spiro ring compounds and methods of their usein treating HCV infection. Specifically, it has been found that thespiro ring compounds disclosed herein, and compositions thereof, areeffective as inhibitors of HCV infection, especially the non-structural5A (NS5A) protein of HCV.

In one aspect, provided herein are compounds having Formula (I) as shownbelow:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein:A is a single bond, alkylene, alkenylene, cycloalkylene,heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—, or—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶, or CR⁷R^(7a);X⁴ is (CR⁷R^(7a))_(n), —Y¹═Y²—, O, S or NR⁶;W is a carbocyclyl or heterocyclyl ring;each Y¹ and Y² is independently N or CR⁷;Z is (CH₂)_(a)—, —CH═CH—, —N═CH—, —(CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or—(CH₂)_(a)—O—(CH₂)_(b);each c and d is independently 1 or 2;each a, b, n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2;each of Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each e and f is independently 0, 1, 2, 3 or 4;each of X and X′ is independently N or CR⁷;each of Y and Y′ is independently H, deuterium, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent groupderived from α-amino acid or an optically isomer thereof, or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;each Q⁴ and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O)₂—;each t is independently 0, 1, 2, 3 or 4;each k is independently 0, 1 or 2;each of R¹, R², R³ and R⁴ is independently H, deuterium, alkyl,heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; orR¹ and R², together with X—CH they are attached to, optionally form a3-8 membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; or R³and R⁴, together with X′—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle;each R⁵ is independently H, deuterium, hydroxy, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy,alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O)_(r)—,alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)— or aminosulfonyl;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N-alkyl, R¹³S(═O)- alkyl,R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy,R¹³R^(13a)N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl,haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro,aralkyl, arylamino, heteroarylamino, arylalkylamino,heteroarylalkylamino, heteroaryloxy, heteroarylalky, arylalkoxy,heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy,heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl,alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy,heterocyclylalkylamino or aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, aliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl or carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N-alkyl, R¹³S(═O)- alkyl,R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy,R¹³R^(13a)N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl,haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro,aralkyl, arylamino, heteroarylamino, arylalkylamino,heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy,heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy,heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl,alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy,heterocyclylalkylamino or aryloxy;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I,aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;each R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl,alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)— or aminosulfonyl;each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl orcycloalkylalkyl;each R¹² is independently R^(13a)R¹³N—, —C(═O)R¹³, —C(═S)R¹³,—C(═O)—O—R¹³, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;or R¹¹ and R¹² are optionally joined to form a 4-7 membered ring; andand each R¹³ and R^(13a) is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; withthe proviso that where R¹³ and R^(13a) are bonded to the same nitrogenatom, R¹³ and R^(13a), together with the nitrogen atom they are attachedto, optionally form a substituted or unsubstituted 3-8 membered ring,spiro bicyclic ring or fused bicyclic ring;wherein each of alkylene, alkenylene, cycloalkylene,heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—NR¹¹—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹²,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²,NR⁶, CR⁷R^(7a), CR⁷, —(CH₂)_(a)—, —CH═CH—, —N═CH—,—(CH₂)_(a)—N(R⁵)—(CH₂)_(b)—, —(CH₂)_(a)—O—(CH₂)_(b)—, R^(13a)R¹³N—,—C(═O)R¹³, —C(═S)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, alkyl-OC(═O)—,alkyl-C(═O)—, alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R^(13a)R¹³N-alkyl,R¹³S(═O)-alkyl, R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy,R¹³S(═O)-alkoxy, R¹³R^(13a)N—C(═O)-alkylamino, alkyl, heteroalkyl,carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,α-amino acid, C₅₋₁₂ fused bicycle, C₅₋₁₂ fused heterobicycle, C₅₋₁₂spiro bicycle, C₅₋₁₂ spiro heterobicycle, alkoxy, aliphatic,haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic,alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino,heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy,heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino andaryloxy is optionally substituted with one or more substituentsindependently selected from hydroxy, deuterium, amino, halo, cyano,aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl,alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O),carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—,alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—, hydroxy-substitutedalkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂— or carboxyl-substitutedalkoxy.

In some embodiments, W is a C₃₋₈ carbocyclyl or C₂₋₁₀ heterocyclyl ring.

In some embodiments,

wherein each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each X⁶ is independently CR⁷R^(7a), O, S or NR⁶;each Y¹ and Y² is independently N or CR⁷;each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each e and f is independently 0, 1, 2, 3 or 4;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl,C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl; andeach R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments,

wherein each Y¹ and Y² is independently N or CH;each X⁶ is independently CR⁷R^(7a), O, S, or NR⁶;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R¹³, —OC(═O)NR¹³R¹³,—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R¹³, —N(R¹³)C(═O)OR^(13a),—N(R¹³C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro or C₁₋₆ alkylamino;R⁶ is H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(O)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocycyl-C₁₋₆-alkyl, C₃₋₈cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl; andeach of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments, wherein A is a single bond, C₁₋₆ alkylene, C₂₋₆alkenylene, C₃₋₈ cycloalkylene, C₂₋₁₀ heterocycloalkylene,—(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—, —(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—, or —(CR⁸R^(8a)),—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶ or CR⁷R^(7a);

Q⁴ is —C(═O)—, —S(═O)— or —S(═O)₂—;

each e is independently 0, 1, 2, 3 or 4;each Y¹ and Y² is independently N or CR⁷;Z is —(CH₂)_(a)—, —CH═CH—, —N═CH, (CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or—(CH₂)_(a)—O—(CH₂)_(b)—;each c and d is independently 1 or 2;each a b n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2;each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;R⁶ is H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(═O)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N—C₁₋₆-alkyl, R¹³S(═O)—C₁₋₆-alkyl,R¹³R^(13a)N—C(═O)—C₁₋₆-alkyl, R^(13a)R¹³N—C₁₋₆-alkoxy,R¹³S(═O)—C₁₋₆-alkoxy, R¹³R^(13a)N—C(═O)—C₁₋₆-alkoxy, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl,mercapto, nitro, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₆₋₁₀ arylamino, C₁₋₉heteroarylamino or C₆₋₁₀ aryloxy;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring; andeach R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl.

In some embodiments, A is a single bond, —CH₂—, —(CH₂)₂—, —CH═CH—,—CH═CH—CH₂—, —N(R⁵)—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R⁵)—,—OC(═O)N(R⁵)—, —OC(═O)O—, —N(R⁵)C(═O)N(R⁵)—, —(R⁵)N—S(═O)₂—, —S(═O)₂—,—OS(═O)₂—, —(R⁵)N—S(═O)—, —S(═O)—, —OS(═O)—, or A is

A′ is

wherein, X¹ is O or S;

Y¹ is N or CH;

each e is independently 0, 1, 2 or 3;each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;each R⁶ is independently H, deuterium, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆alkylamino-C₁₋₆-alkyl, C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, mercapto or nitro; andeach R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments, wherein each of R¹, R², R³ and R⁴ is independentlyH, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ heterocyclyl, C₁₋₉ heteroaryl or C₆₋₁₀ aryl; or R¹ andR², together with X—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; or R³and R⁴, together with X′—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle.

In other embodiments, R¹ and R², together with X—CH they are attachedto, or R³ and R⁴, together with X′—CH they are attached to, optionallyform a 3-8 membered heterocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle.

In other embodiments, R¹, R² and Y—X—CH together form one of thefollowing monovalent groups:

wherein each R¹⁵ is independently H, deuterium, oxo(═O), F, Cl, Br, I,cyano, hydroxy, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino, C₁₋₃ alkylthio, C₆₋₁₀ arylamino, C₆₋₁₀ aryloxy, C₁₋₉heteroaryl, C₁₋₉ heteroaryloxy, C₁₋₉ heteroaryl-C₁₋₃-alkyl or C₂₋₁₀heterocyclyl;each R⁶ is independently H, deuterium, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₃ alkoxy-C₁₋₃-alkyl, C₁₋₃alkylamino-C₁₋₃-alkyl, C₁₋₃ alkylthio-C₁₋₃-alkyl, C₆₋₁₀ aryl-C₁₋₃-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; andeach n₁ and n₂ is independently 1, 2, 3 or 4.

In other embodiments, R³, R⁴ and Y′—X′—CH together form one of thefollowing monovalent groups:

wherein each R¹⁵ is independently H, deuterium, oxo(═O), F, Cl, Br, I,cyano, hydroxy, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino, C₁₋₃ alkylthio, C₆₋₁₀ arylamino, C₆₋₁₀ aryloxy, C₁₋₉heteroaryl, C₁₋₉ heteroaryloxy, C₁₋₉ heteroaryl-C₁₋₃-alkyl or C₂₋₁₀heterocyclyl;each R⁶ is independently H, deuterium, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₃ alkoxy-C₁₋₃-alkyl, C₁₋₃alkylamino-C₁₋₃-alkyl, C₁₋₃ alkylthio-C₁₋₃-alkyl, C₆₋₁₀ aryl-C₁₋₃-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; andeach n₁ and n₂ is independently 1, 2, 3 or 4.

In some embodiments, the compound may have formula (II):

wherein,

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4;each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each Y¹ and Y² is independently N or CR⁷;A is a single bond, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₃₋₈ cycloalkylene,C₂₋₁₀ heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a)),—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)— S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

X¹ is O, S, NR⁶, or CR⁷R^(7a);

each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— aminosulfonyl;each R^(5a) and R^(6a) is independently H, deuterium, oxo(═O), hydroxy,amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy,C₁₋₆ alkoxyacyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃,mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀ cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆aliphatic, C₂₋₆ heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀ cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl;each R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2; andeach of Y₄ and Y₄′ is independently a single bond, O, S, —(CH₂)_(n)—,—CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—, —CF₂—, —CHR^(5a)—,—CR^(5a)R^(6a)—, —CH₂S(═O)_(r), or —CH₂N(R⁶)—.

In some embodiments, the compound may have formula (II′):

wherein

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4;each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each X⁶ is independently CH₂, O, S or NR⁶;A is a single bond, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₃₋₈ cycloalkylene,C₂₋₁₀ heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p),—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p),—(CR⁸R^(8a))_(n)—S(═O)_(r)O—(CR⁸R^(8a))—,(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p),—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;each R^(5a) and R^(6a) is independently H, deuterium, oxo(═O), hydroxy,amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy,C₁₋₆ alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆alkylamino, C₃₋₁₀ cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆aliphatic, C₂₋₆ heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀ cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl;each R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2; andeach of Y₄ and Y₄′ is independently a single bond, O, S, —(CH₂)_(n)—,—CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—, —CF₂—, —CR^(5a)R^(6a)—, CHR^(5a)—,—CH₂S(═O)_(r), or —CH₂N(R⁶)—.

In other embodiments, the compound may have formula (III):

In other embodiments, the compound may have formula (IV):

Wherein each of Q² and Q³ is independently O, S, C(═O), NR⁶, or CH₂.

In other embodiments, the compound may have formula (V):

wherein e is 1, 2, 3 or 4.

In other embodiments, the compound may have formula (III′):

In other embodiments, the compound may have formula (IV′):

wherein each of Q² and Q³ is independently O, S, C(═O), NR, or CH₂.

In other embodiments, the compound may have formula (V′):

wherein e is 1, 2, 3 or 4.

In some embodiments, each of Y and Y′ is independently a monovalentgroup derived from an α-amino acid which is optionally substituted withone or more substituents independently selected from deuterium, F, Cl,Br, I, hydroxy or cyano.

In other embodiments, the α-amino acid is isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophane, valine, alanine,asparagine, aspartic acid, glutamic acid, glutamine, proline, serine,p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine,N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine,homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosineor hydroxyproline.

In other embodiments, the α-amino acid is in the D configuration.

In other embodiments, the α-amino acid is in the L configuration.

In some embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹¹)— (CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]k-C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—C(═O)—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—C(═O)—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—C(═O)—O—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—C(═O)—O—R¹³.

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—R¹² wherein R¹¹ and R¹², together with theatom they are attached to, form a 4-7 membered ring.

In other embodiments, each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H,deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;

each R¹² is independently R^(13a)R¹³N—, —C(═O)R¹³, —C(═S)R¹³,—C(═O)—O—R¹³, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl;or R¹¹ and R¹², together with the atom they are attached to, form a 4-7membered ring;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each t is independently 0, 1, 2, 3 or 4; andeach k is independently 0, 1 or 2.

In other embodiments, each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H,deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl;

each R¹² is independently —C(═O)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;or R¹¹ and R¹², together with the atom they are attached to, form a 4-7membered ring; andeach R¹³ and R^(13a) is independently H, deuterium, methyl, ethyl,propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.

In other embodiments, the compound may have formula (VI):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl; wherein each ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In other embodiments, the compound may have formula (VII):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₃hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl,propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl,piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C₁₋₉ heteroaryl;wherein each of C₁₋₃ hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl,tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl,morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyland C₁₋₉ heteroaryl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano.

In some embodiments, the compound may have formula (VIII):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;each n₂ is independently 1, 2, 3 or 4; andwherein each of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆heteroalkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (IX):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;each n₁ is independently 1, 2, 3 or 4; andwherein each of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆heteroalkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (X):

wherein R^(5a) is H, deuterium, methyl, ethyl, F, Cl, Br or I;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isopropyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, methoxy, ethoxy, benzyl, tert-butoxy and tert-butyl isoptionally substituted with one or more substituents independentlyselected from deuterium, F, Cl, Br, hydroxy or cyano;wherein

wherein Bn is benzyl;

A is

A′ is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In other embodiments, the compound may have formula (XI):

wherein, each R^(5a) is independently H, deuterium, C₁₋₄ alkyl, F, Cl,Br or I;i is 1, 2, 3 or 4;each of Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each of e and f is independently 0, 1, 2, 3 or 4;

Q⁴ is —C(═O)—, —S(═O)— or —S(═O)₂; X¹ is O, NR⁶ or CR⁷R^(7a);

each of Y¹ and Y² is independently N or CR⁷;each R⁶, R⁷ and R^(7a) is independently H, deuterium, C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;each of R¹⁶ and R^(16a) is independently hydroxy, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;wherein each of C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl and C₆₋₁₀ aryloxy is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano;

A is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In other embodiments, each R^(5a) is independently H, deuterium, methyl,ethyl, F, Cl, Br or I;

each R⁷ is independently H, deuterium, methyl, ethyl, isopropyl, phenylor cyclohexyl;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isopropyl, isobutyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy andtert-butyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (X′):

wherein R^(5a) is independently H, deuterium, methyl, ethyl, F, Cl, Bror I;each of Q¹ and Q² is independently CH₂, C(═O), CF₂, O, NR⁶ or S;

X⁶ is O, S, NH or CH₂;

R⁶ is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isobutyl, isopropyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy andtert-butyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano;

A is

A′ is

wherein

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising any one of the above compounds.

In some embodiments, the pharmaceutical composition also comprises apharmaceutically acceptable carrier, excipient, diluent, adjuvant,vehicle or a combination thereof.

In certain embodiments, the pharmaceutical composition disclosed hereinfurther comprises an anti-HCV agent.

In other embodiments, the anti-HCV agent is interferon, ribavirin, IL-2,IL-6, IL-12, a compound that enhances the development of a type 1 helperT cell response, interfering RNA, anti-sense RNA, imiquimod, aninosine-5′-monophosphate dehydrogenase inhibitor, amantadine,rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™),boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir,vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172,vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239,PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805,PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625,ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136,IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189,IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796,HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072,PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667,AZD-2795, TMC647055 or a combination thereof.

In other embodiments, the interferon is interferon α-2b, pegylatedinterferon α, interferon α-2a, pegylated interferon α-2a, consensusinterferon-α, interferon γ or a combination thereof.

In other embodiments, the pharmaceutical composition disclosed hereinfurther comprises at least one HCV inhibitor.

In some embodiments, the HCV inhibitor inhibits at least one of HCVreplication process and HCV viral protein function.

In some embodiments, the HCV replication process is a whole viral cycleconsisting of HCV entry, uncoating, translation, replication, assemblyand egress.

In some embodiments, the HCV viral protein is metalloproteinase, NS2,NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES)or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication.

In another aspect, use of the compound or the pharmaceutical compositionin inhibiting at least one of HCV replication process and HCV viralprotein function is provided.

In some embodiments, the HCV replication process is a whole viral cycleconsisting of HCV entry, uncoating, translation, replication, assemblyand egress.

In some embodiments, the HCV viral protein is metalloproteinase, NS2,NS3, NS4A, NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES)or inosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication.

In another aspect, use of the compound or the pharmaceutical compositiondisclosed herein for preventing, managing, treating or lessening theseverity of HCV infection and a HCV disorder in a patient is provided,which comprises administering a therapeutically effective amount of the(a) compound or pharmaceutical composition disclosed herein to thepatient.

In another aspect, the compound or the pharmaceutical compositiondisclosed herein for use in inhibiting at least one of HCV replicationprocess and HCV viral protein function is provided. In some embodiments,the HCV replication process is a whole viral cycle consisting of HCVentry, uncoating, translation, replication, assembly and egress; In someembodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A,NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) orinosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication.

In another aspect, the compound or the pharmaceutical compositiondisclosed herein for use in preventing, managing, treating or lesseningthe severity of HCV infection or a HCV disorder in a patient isprovided.

In another aspect, a method of inhibiting at least one of HCVreplication process and HCV viral protein function is provided. In someembodiments, the HCV replication process is a whole viral cycleconsisting of HCV entry, uncoating, translation, replication, assemblyand egress; In some embodiments, the HCV viral protein ismetalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or an internalribosome entry site (IRES) or inosine-5′-monophosphate dehydrogenase(IMPDH) required in HCV viral replication.

In another aspect, a method of preventing, managing, treating orlessening the severity of HCV infection or a HCV disorder in a patientis provided, which comprises administering a therapeutically effectiveamount of the (a) compound or pharmaceutical composition disclosedherein to the patient.

In another aspect, provided herein include methods of preparing, methodsof separating, and methods of purifying compounds of Formula (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (II′), (III′),(IV′), (V′) or (X′).

The foregoing merely summarizes certain aspects disclosed herein and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

Reference will now be made in detail to certain embodiments disclosedherein, examples of which are illustrated in the accompanying structuresand formulas. The invention is intended to cover all alternatives,modifications, and equivalents that may be included within the scopedisclosed herein as defined by the claims. One skilled in the art willrecognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice disclosed herein.Described herein is in no way limited to the methods and materials. Inthe event that one or more of the incorporated literature, patents, andsimilar materials differ from or contradict this application, includingbut not limited to defined terms, term usage, described techniques, orthe like, this application controls.

As used herein, the following definitions shall be applied unlessotherwise indicated. For purposes disclosed herein, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, and the Handbook of Chemistry and Physics, 75thEd. 1994. Additionally, general principles of organic chemistry aredescribed in Sorrell et al., “Organic Chemistry”, University ScienceBooks, Sausalito: 1999, and Smith et al., “March's Advanced OrganicChemistry”, John Wiley & Sons, New York: 2007, all of which areincorporated herein by reference in their entireties.

As described herein, compounds may optionally be substituted with one ormore substituents, such as those illustrated above, or as exemplified byparticular classes, subclasses, and species disclosed herein. It will beappreciated that the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted”. Ingeneral, the term “substituted” whether preceded by the term“optionally” or not, refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position. Wherein thesubstituents described herein include, but are not limited to,deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy,alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto,nitro, aryloxy, heteroaryloxy, oxo (═O), carboxy, hydroxy-substitutedalkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—,alkyl-S(═O)₂—, hydroxy-substituted alkyl-S(═O)—, hydroxy-substitutedalkyl-S(═O)₂—, carboxyalkoxy, and the like.

The term “aliphatic” or “aliphatic group” refers to a straight-chain(i.e., unbranched) or branched, substituted or unsubstituted hydrocarbonchain that is completely saturated or that contains one or more units ofunsaturation. Unless otherwise specified, aliphatic groups contain 1-20carbon atoms. In some embodiments, the aliphatic group contains 1-10carbon atoms. In other embodiments, the aliphatic group contains 1-8carbon atoms. In still other embodiments, the aliphatic group contains1-6 carbon atoms, and in yet other embodiments, the aliphatic groupcontains 1-4 carbon atoms. In other embodiments, the aliphatic groupcontains 1-3 carbon atoms. Some non-limiting examples of the aliphaticgroup include linear or branched, substituted or unsubstituted alkyl,alkenyl or alkynyl groups, as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, hexyl, isobutyl, sec-butyl, vinyl, and the like.

The term “haloaliphatic” refers to an aliphatic group substituted withone or more of the same or different halogen atoms (i.e., F, Cl, Br orI), wherein the aliphatic group is as defined herein. Some non-limitingexamples of the haloaliphatic group include trifluoromethyl,trifluoroethyl, chloromethyl, 2-chlorovinyl, and the like.

The term “hydroxyaliphatic” refers to an aliphatic group substitutedwith one or more hydroxy groups, wherein the aliphatic group is asdefined herein. Some non-limiting examples of the hydroxyaliphatic groupinclude hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.

The term “aminoaliphatic” refers to an aliphatic group substituted withone or more amino groups, wherein the aliphatic group is as definedherein. Some non-limiting examples of the aminoaliphatic group includeaminomethyl, 2-aminoethyl, 2-amino isopropyl, and the like.

The term “alkyl” refers to a saturated linear or branched chainmonovalent hydrocarbon radical of one to twenty carbon atoms, or one toten carbon atoms, or one to eight carbon atoms, or one to six carbonatoms, or one to four carbon atoms, or one to three carbon atoms,wherein the alkyl radical may be optionally substituted independentlywith one or more substituents described herein. The examples of thealkyl group include, but are not limited to, methyl (Me, —CH₃), ethyl(Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 1-heptyl, 1-octyl, and the like.The prefix “alk-” refers to inclusive of both straight chain andbranched saturated carbon chain. The term “alkylene” refers to asaturated divalent hydrocarbon group derived from a straight or branchedchain saturated hydrocarbon by the removal of two hydrogen atoms, and isexemplified by methylene, ethylidene, isopropylidene, and the like.

The term “alkenyl” refers to a linear or branched chain monovalenthydrocarbon radical of two to twelve carbon atoms, or two to eightcarbon atoms, or two to six carbon atoms, or two to four carbon atoms,with at least one site of unsaturation, i.e., a carbon-carbon, sp²double bond, wherein the alkenyl radical may be optionally substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Some non-limiting examples ofthe alkenyl group include ethenyl or vinyl (—CH═CH₂), allyl(—CH₂CH═CH₂), and the like.

The term “alkynyl” refers to a linear or branched chain monovalenthydrocarbon radical of two to twelve carbon atoms, or two to eightcarbon atoms, or two to six carbon atoms, or two to four carbon atoms,with at least one site of unsaturation, i.e., a carbon-carbon, sp triplebond, wherein the alkynyl radical may be optionally substitutedindependently with one or more substituents described herein. Somenon-limiting examples of the alkenyl group include ethynyl (—C≡CH),2-propynyl or propargyl (—CH₂C≡CH), and the like.

The term “hydroxy-substituted alkyl” refers to an alkyl groupsubstituted with one or more hydroxy groups, wherein the alkyl group isas defined herein. Some non-limiting examples of the hydroxy-substitutedalkyl group include hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, andthe like.

The term “haloalkyl” refers to an alkyl group substituted with one ormore of the same or different halogen atoms (i.e., F, Cl, Br or I),wherein the alkyl group is as defined herein. Some non-limiting examplesof the haloalkyl group include trifluoromethyl, trifluoroethyl,chloromethyl, fluoromethyl, and the like.

The term “hydroxyalkyl” refers to an alkyl group substituted with one ormore hydroxy groups, wherein the alkyl group is as defined herein. Somenon-limiting examples of the hydroxyalkyl group include hydroxyethyl,2-hydroxypropyl, hydroxymethyl, and the like.

The term “aminoalkyl” refers to an alkyl group substituted with one ormore amino groups, wherein the alkyl group is as defined herein. Somenon-limiting examples of the aminoalkyl group include aminomethyl,2-aminoethyl, 2-amino isopropyl, and the like.

The term “alkylene” refers to a saturated divalent hydrocarbon groupderived from a straight or branched chain saturated hydrocarbon by theremoval of two hydrogen atoms. The alkylene group is optionallysubstituted with one or more substituents. The substituents include, butare not limited to, deuterium, hydroxy, amino, halo, cyano, aryl,heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto,nitro or aryloxy. Some non-limiting examples of the alkylene groupinclude methylene (—CH₂—), ethylidene (—CH₂—CH₂—, CH₃—CH═),isopropylidene, (—CH₂—CH(CH₃)—), 2-methoxy-1,1-propylidene,2-hydroxy-1,1-propylidene, 2-methyl-2-hydroxy-1,1-propylidene, and thelike.

The term “alkenylene” refers to an unsaturated divalent hydrocarbongroup derived from a straight or branched chain alkene by the removal oftwo hydrogen atoms. The alkenylene group is optionally substituted withone or more substituents. The substituents include, but are not limitedto, deuterium, hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy,alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro or aryloxy. Somenon-limiting examples of the alkenylene group include ethenylene(—CH═CH—), isopropenylene (—C(CH₃)═CH—), 3-methoxy-1,1-propenylidene,2-methyl-1,1-butenylidene, and the like.

The term “carbocyclylene” or “cycloalkylene” refers to a saturateddivalent hydrocarbon ring derived from a monocyclic ring having 3 to 12carbon atoms or a bicyclic ring having 7 to 12 carbon atoms by theremoval of two hydrogen atoms, wherein the carbocyclyl group or thecycloalkyl group is as defined herein. Some non-limiting examples of thecarbocyclylene group include cyclopropylidene, cyclobutylene,cyclopentylene, 1-cyclopent-1-enylene, 1-cyclopent-2-enylene, and thelike.

The term “heterocyclylene” refers to a monocyclic, bicyclic or tricyclicring system in which one or more ring members are an independentlyselected heteroatom and that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic, that hastwo points of attachment to the rest of the molecule, wherein theheterocyclyl group is as defined herein. Some non-limiting examples ofthe heterocyclylene group include piperidin-1,4-ylene,piperazin-1,4-ylene, tetrahydrofuran-2,4-ylene,tetrahydrofuran-3,4-ylene, azetidin-1,3-ylene, pyrrolidin-1,3-ylene, andthe like.

The term “heterocyclylalkylene” refers to a divalent group derived froma heterocyclylalkyl by the removal of two hydrogen atoms, wherein theheterocyclylalkyl group is as defined herein. Some non-limiting examplesof the heterocyclylalkylene group include morpholin-4-methylmethylene,piperidin-N-methylmethylene, and the like.

The term “haloalkylene” refers to haloalkyl system having two connectionpoints connected to the rest of the molecule, wherein the alkylene groupis as defined herein. Some non-limiting examples of the haloalkylenegroup include difluoromethylene (—CF₂—).

The term “arylene” refers to aryl system having two connection pointsconnected to the rest of the molecule, wherein the aryl radical is asdefined herein. Some non-limiting examples of the arylene group includephenylene, p-fluorophenylene, and the like.

The term “aralkylene” refers to aralkyl system having two connectionpoints connected to the rest of the molecule, wherein the aralkylradical is as defined herein. Some non-limiting examples of thearalkylene group include benzylene, phenylethylene, and the like.

The term “heteroarylene” refers to heteroaryl system having twoconnection points connected to the rest of the molecule, wherein theheteroaryl radical is as defined herein. Some non-limiting examples ofthe heteroarylene group include pyridylene, pyrrylene, thiazolylene,imidazolylene, and the like.

The term “heteroarylalkylene” refers to heteroarylalkyl system havingtwo connection points connected to the rest of the molecule, wherein theheteroarylalkyl group is as defined herein. Some non-limiting examplesof the heteroarylalkylene group include pyridin-2-ethylene,thiazol-2-methylene, imidazol-2-ethylene, pyrimidin-2-methylene, and thelike.

The term “fused bicyclylene” refers to fused bicyclyl system having twoconnection points connected to the rest of the molecule, wherein thefused bicyclyl group is as defined herein. Some non-limiting examples ofthe fused bicyclylene group include bicyclo[3.1.0]hexane-3,6-ylene.

The term “fused heterobicyclylene” refers to fused heterobicyclyl systemhaving two connection points connected to the rest of the molecule,wherein the fused heterobicyclyl group is as defined herein. Somenon-limiting examples of the fused heterobicyclylene group include3-azabicyclo[3.1.0]hexane-3,6-ylene.

The term “fused bicyclylalkylene” refers to fused bicyclylalkyl systemhaving two connection points connected to the rest of the molecule,wherein the fused bicyclylalkyl group is as defined herein.

The term “fused heterobicyclylalkylene” refers to fusedheterobicyclylalkyl system having two connection points connected to therest of the molecule, wherein the fused heterobicyclylalkyl group is asdefined herein.

The term “spiro bicyclylene” refers to spiro bicyclyl system having twoconnection points connected to the rest of the molecule, wherein thespiro bicyclyl group is as defined herein. Some non-limiting examples ofthe spiro bicyclylene group include 5-spiro[2,4]heptane-5,7-ylene,spiro[4,4]nonane-2,7-ylene, and the like.

The term “spiro heterobicyclylene” refers to spiro heterobicyclyl systemhaving two connection points connected to the rest of the molecule,wherein the spiro heterobicyclyl group is as defined herein. Somenon-limiting examples of the spiro heterobicyclylene group include5-azaspiro[2,4]heptane-5,7-ylene, 2-azaspiro[4,4]nonane-2,7-ylene, andthe like.

The term “spiro bicyclylalkylene” refers to spiro bicyclylalkyl systemhaving two connection points connected to the rest of the molecule,wherein the spiro bicyclylalkyl group is as defined herein.

The term “spiro heterobicyclylalkylene” refers to spiroheterobicyclylalkyl system having two connection points connected to therest of the molecule, wherein the spiro heterobicyclylalkyl group is asdefined herein.

The term “heteroalkyl” refers to alkyl chain inserted with one or moreheteroatoms, wherein the alkyl and heteroatom are as defined herein.Unless otherwise specified, the heteroalkyl group contains 1-10 carbonatoms. In other embodiments, the heteroalkyl group contains 1-8 carbonatoms. In still other embodiments, the heteroalkyl group contains 1-6carbon atoms, and in yet other embodiments, the heteroalkyl groupcontains 1-4 carbon atoms. In other embodiments, the heteroalkyl groupcontains 1-3 carbon atoms. Some non-limiting examples of the spirobicyclylene group include CH₃OCH₂—, CH₃CH₂OCH₂—, CH₃SCH₂—, (CH₃)₂NCH₂—,(CH₃)₂CH₂OCH₂—, CH₃OCH₂CH₂—, CH₃CH₂OCH₂CH₂—, and the like.

The term “cycloaliphatic”, “carbocycle”, “carbocyclyl” or “cycloalkyl”refers to a monovalent or multivalent non-aromatic, saturated orpartially unsaturated ring exclusive of heteroatoms, having 3 to 12carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclicring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, forexample, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicycliccarbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6]or [6,6] system. Some non-limiting examples of the cycloaliphatic groupinclude cycloalkyl, cycloalkenyl and cycloalkynyl. Further examples ofthe cycloaliphatic group include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl,cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl,1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Theterm “cycloaliphatic”, “carbocycle”, “carbocyclyl” or “cycloalkyl” maybe substituted or unsubstituted, wherein the substituent may be, but isnot limited to, deuterium, hydroxy, amino, halo, cyano, aryl,heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl,mercapto, nitro, aryloxy, hydroxy-substituted alkoxy,hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—,alkyl-S(═O)₂—, hydroxy-substituted alkyl-S(═O)—, hydroxy-substitutedalkyl-S(═O)₂—, carboxyalkoxy, and the like.

The term “cycloalkyloxy” or “carbocyclyloxy” refers to an optionallysubstituted cycloalkyl or carbocyclyl radical, as defined herein,attached to an oxygen atom, wherein the oxygen atom serves as theattaching point to the rest of the molecule. Some non-limiting examplesof the cycloalkyloxy group include cyclopropyloxy, cyclopentyloxy,cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.

The term “cycloalkylamino” refers to an amino group substituted with oneor two optionally substituted cycloalkyl radicals, wherein thecycloalkyl group is as defined herein. Some non-limiting examples of thecycloalkylamino group include cyclopropylamino, cyclopentylamino,cyclohexylamino, hydroxy-substituted cyclopropylamino,dicyclohexylamino, dicyclopropylamino, and the like.

The term “carbocyclyloxyalkoxy” refers to an alkoxy group substitutedwith one or more carbocyclyloxy groups, wherein the alkoxy group andcarbocyclyloxy group are as defined herein. Some non-limiting examplesof the carbocyclyloxyalkoxy group include cyclopropyloxymethoxy,cyclopropyloxyethoxy, cyclopentyloxyethoxy, cyclohexyloxyethoxy,cyclohexenyl-3-oxyethoxy, and the like.

The term “cycloalkyloxyaliphatic” refers to an aliphatic groupsubstituted with one or more optionally substituted cycloalkyloxygroups, wherein the aliphatic group and cycloalkyloxy group are asdefined herein. Some non-limiting examples of the cycloalkyloxyaliphaticgroup include cyclopropyloxymethyl, cyclopropyloxyethyl,cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl,halocyclopropyloxyethyl, and the like.

The term “cycloalkylaminoaliphatic” refers to an aliphatic groupsubstituted with one or more optionally substituted cycloalkylaminogroups, wherein the aliphatic group and cycloalkylamino group are asdefined herein. Some non-limiting examples of thecycloalkylaminoaliphatic group include cyclopropylaminomethyl,cyclopropylaminoethyl, cyclopentylaminomethyl, cyclopentylaminoethyl,cyclohexylaminoethyl, halocyclopropylaminoethyl, and the like.

The term “cycloalkylaliphatic” refers to an aliphatic group substitutedwith one or more cycloalkyl groups, wherein the cycloalkyl group andaliphatic group are as defined herein. Some non-limiting examples of thecycloalkylaliphatic group include cyclopropylmethyl, cyclopropylethyl,cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.

The term “cycloalkylalkoxy” (“carbocyclylalkoxy”) refers to an alkoxygroup substituted with one or more cycloalkyl (carbocyclyl) groups,wherein the cycloalkyl (carbocyclyl) group and alkoxy group are asdefined herein. Some non-limiting examples of the cycloalkylalkoxy groupinclude cyclopropylmethoxy, cyclopropylethoxy, cyclopentylethoxy,cyclohexylethoxy, cyclohexylmethoxy, cyclopropylpropoxy, and the like.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic” or“heterocyclic” as used interchangeably herein refers to a monocyclic,bicyclic or tricyclic ring system in which one or more ring members arean independently selected heteroatom and that is completely saturated orthat contains one or more units of unsaturation, but not aromatic havinga single point of attachment to the rest of the molecule. One or morering atoms are optionally substituted independently with one or moresubstituents described herein. In some embodiments, the “heterocycle”,“heterocyclyl”, “heterocycloaliphatic” or “heterocyclic” group is amonocycle having 3 to 7 ring members (e.g., 1 to 6 carbon atoms and 1 to3 heteroatoms selected from N, O, P or S, wherein the S or P isoptionally substituted with one or more oxo to provide the group SO orSO₂, PO or PO₂, with the proviso that when the ring is a 3-memberedring, there is only one heteroatom) or a bicycle having 7 to 10 ringmembers (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected fromN, O, P or S, wherein the S or P is optionally substituted with one ormore oxo to provide the group SO or SO₂, PO or PO₂).

The heterocyclyl may be a carbon radical or heteroatom radical.“Heterocyclyl” also includes radicals where heterocycle radicals arefused with a saturated, partially unsaturated ring or heterocyclic ring.Some non-limiting examples of the heterocyclic ring includepyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidyl,morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl,piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, epoxypropyl (oxiranyl), azepanyl, oxepanyl, thiepanyl,4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl,diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl,2H-indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolan-2-yl, 1,3-dioxopenyl,pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl,pyrazolidinylimidazolinyl, imidazolidinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiazinyl, 1,1-dioxo-2-yl,4-hydroxy-1,4-azaphosphine-4-oxide-1-yl,2-hydroxy-1-(piperazin-1-yl)ethanone-4-yl,2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4-yl,5,6-dihydro-4H-1,2,4-oxadiazine-4-yl, 2-hydroxy-1-(5,6-diludine-1(2H)-yl)ethanone-4-yl, 3-azabicyclo[3,1,0]hexyl,3-azabicyclo[4,1,0]heptyl, azabicyclo[2,2,2]hexyl,2-methyl-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-c]pyrimidin-6-yl,4,5,6,7-teterhydro-isoxazole[4,3-c]pyridin-5-yl,3H-indoxyl-2-oxo-5-azabicyclo[2,2,1]heptan-5-yl,2-oxo-5-azabicyclo[2,2,2]octan-5-yl, quinolizinyl and N-pyridyl urea.Some non-limiting examples of a heterocyclic ring include1,1-dioxo-thiomorpholinyl and heterocyclic group wherein 2 carbon atomson the ring are substituted with oxo (═O) moieties are pyrimidindionyl.The heterocyclic group herein may be substituted or unsubstituted,wherein the substituent may be, but is not limited to, deuterium, oxo(═O), hydroxy, amino, halo, cyano, heteroaryl, alkoxy, alkylamino,alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy,hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—,alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—, hydroxy-substitutedalkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂—, carboxyalkoxy, and thelike.

The term “heterocyclylalkyl” refers to heterocyclic-substituted alkylradical. The term “heterocyclylalkoxy” refers toheterocyclic-substituted alkoxy radical wherein oxygen atom serves asthe attaching point to the rest of the molecule. The term“heterocyclylalkylamino” refers to heterocyclic-substituted alkylaminoradical wherein nitrogen atom serves as the attaching point to the restof the molecule. Wherein the heterocyclyl, alkyl, alkoxy and alkylaminogroup are as defined herein. Some non-limiting examples of theheterocyclylalkyl group include pyrrol-2-ylmethyl, morpholin-4-ylethyl,morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino,and the like.

The term “heterocyclylaliphatic” refers to heterocyclic-substitutedaliphatic group, wherein the heterocyclic group and aliphatic group areas defined herein. Some non-limiting examples of theheterocyclylaliphatic group include pyrrol-2-ylmethyl,piperidin-2-ylethyl, piperazin-2-ylethyl, piperidin-2-ylmethyl, and thelike.

The term “heterocyclyloxy” refers to optionally substituted heterocyclylradical, as defined herein, connected to an oxygen atom, and the oxygenatom serves as the attaching point to the rest of the molecule. Somenon-limiting examples of the heterocyclyloxy group includepyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy,piperazin-2-yloxy, piperidin-4-yloxy, and the like.

The term “heterocyclylamino” refers to an amino group substituted withone or two heterocyclyl groups, wherein nitrogen atom serves as theattaching point to the rest of the molecule and the heterocyclyl groupis as defined herein. Some non-limiting examples of theheterocyclylamino group include pyrrol-2-ylamino, pyrrol-3-ylamino,piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino,piperazin-2-ylamino, dipyrrol-2-ylamino, and the like.

The term “heterocyclyloxyalkoxy” refers to an alkoxy radical substitutedwith one or more heterocyclyloxy groups, wherein the alkoxy group andheterocyclyloxy group are as defined herein. Some non-limiting examplesof the heterocyclyloxyalkoxy group include pyrrol-2-yloxymethoxy,pyrrol-3-yloxyethoxy, piperidin-2-yloxyethoxy, piperidin-3-yloxyethoxy,piperazin-2-yloxymethoxy, piperidin-4-yloxyethoxy, and the like.

The term “heterocyclyloxyaliphatic” refers to an aliphatic groupsubstituted with one or more heterocyclyloxy groups, wherein thealiphatic group and heterocyclyloxy group are as defined herein. Somenon-limiting examples of the heterocyclyloxyaliphatic group includepyrrol-2-yloxymethyl, piperazin-3-yloxyethyl, piperazin-2-yloxyethyl,morpholin-2-yloxymethyl, piperidin-2-yloxyethyl, and the like.

The term “heterocyclylaminoaliphatic” refers to an aliphatic groupsubstituted with one or more heterocyclylamino groups, wherein thealiphatic group and heterocyclylamino group are as defined herein. Somenon-limiting examples of the heterocyclylaminoaliphatic group includepyrrol-2-ylaminomethyl, piperazin-3-lyaminoethyl,piperazin-2-lyaminoethyl, piperidin-2-lyaminoethyl,morpholin-2-lyaminomethyl, and the like.

The term “heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus or silicon, including any oxidized form of nitrogen, sulfuror phosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example, N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as inN-substituted pyrrolidinyl).

The term “halogen” or “halo” refers to F, Cl, Br or I.

The term “unsaturated” as used herein, refers to a moiety having one ormore units of unsaturation.

The term “alkoxy” refers to an alkyl group, as previously defined,attached to the principal carbon chain through an oxygen atom. Somenon-limiting examples of the alkoxy group include methoxy, ethoxy,propoxy, butoxy, and the like. And the alkoxy defined above may besubstituted or unsubstituted, wherein the substituent may be, but is notlimited to, deuterium, hydroxy, amino, halo, cyano, alkoxy, alkyl,alkenyl, alkynyl, mercapto, nitro, and the like.

The term “hydroxy-substituted alkoxy” or “hydroxyalkoxy” refers to analkoxy group substituted with one or more hydroxy groups, wherein thealkoxy group is as defined above. Some non-limiting examples of thehydroxyalkoxy group include hydroxymethoxy, 2-hydroxyethoxy,2-hydroxypropoxy, 2-hydroxyisopropoxy, and the like.

The term “aminoalkoxy” refers to an alkoxy group substituted with one ormore amino groups, wherein the alkoxy group is as defined above. Somenon-limiting examples of the aminoalkoxy group include aminomethoxy,2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, and the like.

The term “azidoalkoxy” refers to an alkoxy group substituted with one ormore azido groups, wherein the alkoxy group is as defined above. Somenon-limiting examples of the azidoalkoxy group include 2-azidoethoxy,3-azidopropoxy, 2-azidopropoxy, and the like.

The term “alkoxyalkoxy” refers to an alkoxy group substituted with oneor more alkoxy groups, wherein the alkoxy group is as defined above.Some non-limiting examples of the alkoxyalkoxy group includemethoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy,ethoxypropoxy, and the like.

The term “alkoxyaliphatic” refers to an aliphatic group substituted withone or more alkoxy groups, wherein the aliphatic group and alkoxy groupare as defined herein. Some non-limiting examples of the alkoxyaliphaticgroup include methoxymethyl, ethoxymethyl, ethoxyethyl, ethoxypropenyl,and the like.

The term “alkylaminoaliphatic” refers to an aliphatic group substitutedwith one or more alkylamino groups, wherein the aliphatic group andalkylamino group are as defined herein. Some non-limiting examples ofthe alkylaminoaliphatic group include dimethylaminoethyl,methylaminoethyl, diethylaminomethyl, diethylaminoethyl, and the like.

The term “alkylthioaliphatic” refers to an aliphatic group substitutedwith one or more alkylthio groups, wherein the aliphatic group andalkylthio group are as defined herein. Some non-limiting examples of thealkylthioaliphatic group include methylthioethyl, methylthiopropyl,ethylthioethyl, methylthiopropenyl, and the like.

The term “haloalkyl”, “haloalkenyl” or “haloalkoxy” refers to an alkylgroup, alkenyl group or alkoxy group substituted with one or morehalogen atoms. Some non-limiting examples of the haloalkyl group includetrifluoromethyl, 2-chloro-ethenyl, trifluoromethoxy, and the like.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “arylalkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclicand tricyclic carbocyclic ring systems having a total of six to fourteenring members, wherein at least one ring in the system is aromatic,wherein each ring in the system contains 3 to 7 ring members and thathas a single point of attachment to the rest of the molecule. The term“aryl” may be used interchangeably with the term “aryl ring”. Somenon-limiting examples of the aryl ring include phenyl, naphthyl andanthryl. The aryl may be substituted or unsubstituted, wherein thesubstituents include, but are not limited to, deuterium, hydroxy, amino,halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl,alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substitutedalkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—,alkyl-S(═O)₂—, hydroxy-substituted alkyl-S(═O)—, hydroxy-substitutedalkyl-S(═O)₂—, carboxyalkoxy, and the like.

The term “arylaliphatic” refers to an aliphatic group substituted withone or more optionally substituted aryl groups, wherein the aliphaticgroup and the aryl group are as defined herein. Some non-limitingexamples of the arylaliphatic group include phenylethyl, benzyl,(p-tolyl)ethyl, styryl, and the like.

The term “aryloxy” refers to optionally substituted aryl radicals, asdefined herein, attached to an oxygen atom, wherein the oxygen atomserves as the attaching point to the rest of the molecule. Wherein thearyl radical is as defined herein. Some non-limiting examples of thearyloxy group include phenyloxy, methylphenyloxy, ethylphenyloxy, andthe like.

The term “arylamino” refers to an amino group substituted with one ortwo optionally substituted aryl groups, wherein the aryl group is asdefined herein. Some non-limiting examples of the arylamino groupinclude phenylamino, (p-fluorophenyl)amino, diphenylamino, ditolylamino,(di-p-tolyl)amino, and the like.

The term “aryloxyalkoxy” refers to an alkoxy group substituted with oneor more optionally substituted aryloxy groups, wherein the alkoxy groupand the aryloxy group are as defined herein. Some non-limiting examplesof the aryloxyalkoxy group include phenyloxymethoxy, phenyloxyethoxy,phenyloxypropoxy, and the like.

The term “aryloxyaliphatic” refers to an aliphatic group substitutedwith one or more optionally substituted aryloxy groups, wherein thearyloxy group and the aliphatic group are as defined herein. Somenon-limiting examples of the aryloxyaliphatic group includephenyloxymethyl, phenyloxyethyl, phenyloxypropyl, and the like.

The term “arylaminoaliphatic” refers to an aliphatic group substitutedwith one or more optionally substituted arylamino groups, wherein thearylamino group and the aliphatic group are as defined herein. Somenon-limiting examples of the arylaminoaliphatic group includephenylaminomethyl, phenylaminoethyl, tolylaminoethyl, phenylaminopropyl,phenylaminoallyl, and the like.

The term “arylalkoxy” refers to an alkoxy group substituted with one ormore optionally substituted aryl groups, wherein the aryl group and thealkoxy group are as defined herein. Some non-limiting examples of thearylalkoxy group include phenylmethoxy, phenylethoxy, (p-tolyl)methoxy,phenylpropoxy, and the like.

The term “arylalkylamino” refers to an alkylamino group substituted withone or more optionally substituted aryl groups, wherein the aryl groupand the alkylamino group are as defined herein. Some non-limitingexamples of the aryloxyalkoxy group include phenylmethylamino,phenylethylamino, phenylpropylamino, (p-tolyl)methylamino, and the like.

The term “heteroaryl” used alone or as part of a larger moiety as in“heteroarylalkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, and atleast one ring in the system is inclusive of one or more heteroatoms,wherein each ring in the system contains 3 to 7 ring members and thathas a single point of attachment to the rest of the molecule. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or “heteroaromatic compound”. The heteroaryl defined herein may besubstituted or unsubstituted, wherein the substituents include, but arenot limited to, deuterium, hydroxy, amino, halo, cyano, aryl,heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl,mercapto, nitro, aryloxy, hydroxy-substituted alkoxy,hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—,alkyl-S(═O)₂—, hydroxy-substituted alkyl-S(═O)—, hydroxy-substitutedalkyl-S(═O)₂—, carboxyalkoxy, and the like.

Some non-limiting examples of the suitable heteroaryl ring include thefollowing monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl-5-yl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl),triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl,pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl,benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl, and the followingbicycles: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (e.g.,2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl,4-quinolinyl) or isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinylor 4-isoquinolinyl).

The term “heteroaryloxy” refers to an optionally substituted heteroarylradical, as defined herein, attached to an oxygen atom, wherein theoxygen atom serves as the attaching point to the rest of the molecule.Some non-limiting examples of the heteroaryloxy group includepyrid-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy, andthe like.

The term “heteroaryloxyaliphatic” refers to an aliphatic groupsubstituted with one or more optionally substituted heteroaryloxygroups, wherein the aliphatic group and the heteroaryloxy group are asdefined herein. Some non-limiting examples of the heteroaryloxyaliphaticgroup include pyrid-2-yloxyethyl, thiazol-2-yloxymethyl,imidazol-2-yloxyethyl, pyrimidin-2-yloxypropyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such as“alkylsulfonyl”, respectively refers to divalent radicals —SO₂—.

The term “alkylsulfonyl”, refers to a sulfonyl radical substituted withan alkyl radical, forming an alkylsulfonyl (—SO₂-alkyl, such as—SO₂CH₃).

The term “sulfamyl”, “aminosulfonyl” or “sulfonamidyl” refers to asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, refers to —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl” or “carbonyloxy”, refers to —(C═O)—.

The term “carboxyalkoxy” refers to an alkoxy group substituted with oneor more carboxy groups, wherein the alkoxy group and the carboxy groupare as defined herein. Some non-limiting examples includecarboxymethoxy, carboxyethoxy, and the like.

The term “aralkyl” or “arylalkyl” refers to aryl-substituted alkylradicals. In some embodiments, the aralkyl radical includes “loweraralkyl” radicals having aryl radicals attached to alkyl radicals havingone to six carbon atoms. In other embodiments, the aralkyl radicalincludes “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Some non-limiting examples of such radical includebenzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl can beadditionally substituted with halo, alkyl, alkoxy, haloalkyl orhaloalkoxy.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. In some embodiments, the alkylthio radical includes loweralkylthio radicals having one to three carbon atoms. Some non-limitingexamples of “alkylthio” include methylthio (CH₃S—).

The term “haloalkylthio” refers to radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.In some embodiments, the haloalkylthio radical includes lowerhaloalkylthio radicals having one to three carbon atoms. Somenon-limiting examples of “haloalkylthio” include trifluoromethylthio.

The term “alkylamino” refers to “N-alkylamino” and “N,N-dialkylamino”,wherein amino groups are independently substituted with one alkylradical or with two alkyl radicals, respectively. In some embodiments,the alkylamino radical includes lower alkylamino radicals having one ortwo alkyl radicals of one to six carbon atoms, attached to a nitrogenatom. In other embodiments, the alkylamino radical includes loweralkylamino radicals having one to three carbon atoms. Some non-limitingexamples of the suitable alkylamino radical include mono or dialkylaminosuch as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino, and the like.

The term “alkylaminohaloalkoxy” refers to a haloalkoxy group substitutedwith one or more alkylamino groups, wherein the haloalkoxy group and thealkylamino group are as defined herein. Some non-limiting examples ofthe alkylaminohaloalkoxy group include methylaminodifluoromethoxy,ethylaminotrifluoromethoxy, and the like.

The term “heteroarylamino” refers to amino groups substituted with oneor two heteroaryl radicals, wherein the heteroaryl radical is as definedherein. Some non-limiting examples of the heteroarylamino includeN-thienylamino. In some embodiments, the “heteroarylamino” radical maybe further substituted on the heteroaryl ring portion of the radical.

The term “heteroarylaliphatic” refers to aliphatic groups substitutedwith one or more heteroaryl radicals, wherein the heteroaryl group andthe aliphatic group are as defined herein. Some non-limiting examples ofthe heteroarylaliphatic group include thiophen-2-ylpropenyl,pyridin-4-ylethyl, imidazol-2-ylmethyl, furan-2-ylethyl,indol-3-ylmethyl, and the like.

The term “heteroarylalkyl” refers to alkyl groups substituted with oneor more heteroaryl radicals, wherein the heteroaryl group and the alkylgroup are as defined herein. Some non-limiting examples of theheteroarylalkyl group include imidazol-2-ylmethyl, furan-2-ylethyl,indol-3-ylmethyl, and the like.

The term “heteroarylalkylamino” refers to nitrogen-containingheteroarylalkyl radicals attached through a nitrogen atom to otherradicals, wherein the heteroarylalkyl radical is as defined herein. Somenon-limiting examples of the heteroarylalkylamino group includepyridin-2-ylmethylamino, thiazol-2-ylethylamino,imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino,pyrimidin-2-ylmethylamino, and the like.

The term “aminoalkyl” refers to a linear or branched alkyl radicalhaving one to ten carbon atoms, substituted with one or more aminoradicals. In some embodiments, the aminoalkyl radical includes “loweraminoalkyl” radicals having one to six carbon atoms and one or moreamino radicals. Some non-limiting examples of such radical includeaminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term “alkylaminoalkyl” refers to alkyl radicals substituted withalkylamino radicals. In some embodiments, the alkylaminoalkyl radicalincludes “lower alkylaminoalkyl” radicals having alkyl radicals of oneto six carbon atoms. In other embodiments, the alkylaminoalkyl radicalincludes lower alkylaminoalkyl radicals having alkyl radicals of one tothree carbon atoms. Some non-limiting examples of the suitablealkylaminoalkyl radical may be mono and dialkyl substituted, such asN-methylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminomethyl, andthe like.

The term “carboxyalkyl” refers to a linear or branched alkyl radicalhaving one to ten carbon atoms substituted with one or more carboxyradicals. Some non-limiting examples of such radical includecarboxymethyl, carboxypropyl, and the like.

The term “aryloxy” refers to optionally substituted aryl radicals, asdefined above, attached to an oxygen atom, wherein the oxygen atomserves as the attaching point to the rest of the molecule. Somenon-limiting examples of such radical include phenoxy.

The term “heteroarylalkoxy” refers to oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals, wherein theheteroarylalkyl radical is as defined herein. Some non-limiting examplesof such radical include pyridin-2-ylmethoxy, thiazol-2-ylethoxy,imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, andthe like.

The term “cycloalkylalkyl” refers to cycloalkyl-substituted alkylradicals. Some non-limiting examples of such radical includecyclohexylmethyl. The cycloalkyl in the radicals may be additionallysubstituted with deuterium, halo, alkyl, alkoxy or hydroxy.

The term “fused bicyclic”, “fused cyclic”, “fused bicyclyl” or “fusedcyclyl” refers to unsaturated or saturated fused cyclic system andbridged ring system that is not aromatic. For example, as depicted below(Formula (a1)), ring A1 and ring A2 share a bond that is a alkyl orheteroalkyl chain, wherein j is 0, 1, 2, 3 or 4. Such a system maycontain isolated or conjugated unsaturation, but not aromatic orheteroaromatic rings in its core structure (but may have aromaticsubstitution thereon). Each cyclic ring in a fused bicyclyl can beeither a carbocyclic or a heteroalicyclic. Some non-limiting examples ofthe fused bicyclic ring system or bridged ring system includehexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fusedbicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane,and 1,2,3,4,4a,5,8,8a-octahydro-naphthalene. The fused bicyclyl definedherein may be substituted or unsubstituted, wherein the substituentsinclude, but are not limited to, deuterium, oxo (═O), hydroxy, amino,halo, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl,alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substitutedalkoxy, hydroxy-substituted alkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—,alkyl-S(═O)₂—, hydroxy-substituted alkyl-S(═O)—, hydroxy-substitutedalkyl-S(═O)₂—, carboxyalkoxy, and the like.

The term “fused heterobicyclyl” refers to unsaturated or saturated fusedcyclic system and bridged ring system that is not aromatic. Such asystem may contain isolated or conjugated unsaturation, but not aromaticor heteroaromatic rings in its core structure (but may have aromaticsubstitution thereon). And at least one ring in the system is inclusiveof one or more heteroatoms, wherein each ring in the system contains 3to 7 ring members, e.g., 1 to 6 carbon atoms and 1 to 3 heteroatomsselected from N, O, P or S, wherein the S or P is optionally substitutedwith one or more oxo to provide the group SO or SO₂, PO or PO₂. Somenon-limiting examples of the fused heterobicyclic ring system includehexahydro-furo[3,2-b]furan, 6-azabicyclo[3.2.0]heptane,2-azabicyclo[3.1.0]heptane, 3-azabicyclo[3.1.0]heptane,7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, and the like.The fused heterobicyclyl defined herein may be substituted orunsubstituted, wherein the substituents include, but are not limited to,deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl,alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto,nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substitutedalkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—,hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂—,carboxyalkoxy, and the like.

The term “spirocyclyl”, “spirocyclic”, “spiro bicyclyl” or “spirobicyclic” refers to a ring originating from a particular annular carbonof another ring. For example, as depicted below, ring A and ring B sharea carbon atom between the two saturated ring system, which terms as a“spirocyclyl” or “spiro bicyclyl”. Each cyclic ring in the spirocyclylor spiro bicyclyl can be either a carbocyclic or a heteroalicyclic. Somenon-limiting examples of such radical include2,7-diazaspiro[4.4]non-2-yl, 7-oxo-2-azaspiro[4.5]dec-2-yl,4-azaspiro[2.4]hept-5-yl, 4-oxaspiro[2.4]hept-5-yl,5-azaspiro[2.4]hept-5-yl, spiro[2.4]heptyl, spiro[4.4]nonyl,7-hydroxy-5-azaspiro[2.4]hept-5-yl, and the like. The spirocyclyl orspiro bicyclyl may be substituted or unsubstituted, wherein thesubstituents include, but are not limited to, deuterium, oxo (═O),hydroxy, amino, halo, cyano, aryl, heteroaryl, alkoxy, alkylamino,alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy,hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—,alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—, hydroxy-substitutedalkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂—, carboxyalkoxy, and thelike.

The term “spiro bicyclylene” refers to spiro bicyclyl system having twoconnection points connected to the rest of the molecule, wherein thespiro bicyclyl radical is as defined herein.

The terms “spiro heterobicyclyl” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedabove, ring A and ring B share a carbon atom between the two saturatedring system, which terms as a “spirocyclyl”. And at least one ring inthe system is inclusive of one or more heteroatoms, wherein each ring inthe system contains 3 to 7 ring members, e.g., 1 to 6 carbon atoms and 1to 3 heteroatoms selected from N, O, P or S, wherein the S or P isoptionally substituted with one or more oxo to provide the group SO orSO₂, PO or PO₂. Some non-limiting examples of such radical include4-azaspiro[2,4]hept-5-yl, 4-oxaspiro[2,4]hept-5-yl,5-azaspiro[2,4]hept-5-yl, 7-hydroxy-5-azaspiro[2,4]hept-5-yl,5-azaspiro[2,4]hept-6-yl, 1,4-dioxo-7-azaspiro[4,4]non-8-yl, and thelike. The spiro heterobicyclyl defined herein may be substituted orunsubstituted, wherein the substituents include, but are not limited to,deuterium, oxo (═O), hydroxy, amino, halo, cyano, aryl, heteroaryl,alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto,nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substitutedalkyl-C(═O)—, alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—,hydroxy-substituted alkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂—,carboxyalkoxy, and the like.

As described herein, the group derived from α-amino acid refers to anα-amino acid radical derived from an α-amino acid by the removal of onehydroxy from the carboxy group, which is attached to X or X′, and thegroup derived from α-amino acid is optionally substituted with one ormore substituents, wherein the substituent is deuterium, F, Cl, Br, I,hydroxy or cyano. For example,

As described herein, a bond drawn from a substituent to the center ofone ring within a ring system (as shown in Formula (a)) representssubstitution of the substituent (R^(5a))_(f) at any substitutableposition on the rings (W1, W2, and W). For example, Formula (a)represents possible substitution in any of the positions on the ring W1,W2, and W.

As described herein, two attaching points either E or E′, within a ringsystem (as shown in Formula (b)), attach to the rest of the molecule,e.g., E and E′ may be used interchangeably with each other.

As described herein, a dot line drawn together with a bond within a ringsystem (as shown in Formula (c)) represents either a double bond or asingle bond. For example, structure of Formula (c) represents anystructures selected from Formula (d).

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric orgeometric (or conformational) mixtures of the present compounds arewithin the scope disclosed herein.

Furthermore, what need to be explained is that the phrase “each . . . isindependently” is used interchangeably with the phrase “each (of) . . .and . . . is independently”, unless otherwise stated. It should bebroadly understood that the specific options expressed by the samesymbol are independently of each other in different radicals; or thespecific options expressed by the same symbol are independently of eachother in same radicals. For example, R⁹ of the structure formulas“—U—(CR⁹R^(9a))_(t)—R¹²” and“—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²”,whose specific options are independently of each other; meanwhile,multiple R⁹ of the structure formula“—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²”,whose specific options are independently of each other.

The term “prodrug” refers to a compound that is transformed in vivo intoa compound of formula (I). Such a transformation can be affected, forexample, by hydrolysis in blood or enzymatic transformation of theprodrug form to the parent form in blood or tissue. Prodrugs of thecompounds disclosed herein may be, for example, esters. Esters that maybe utilized as prodrugs in the present invention are phenyl esters,aliphatic (C₁-C₂₄) esters, acyloxymethyl esters, carbonates, carbamatesand amino acid esters. For example, a compound disclosed herein thatcontains an OH group may be acylated at this position in its prodrugform. Other prodrug forms include phosphates, such as, for example thosephosphates resulting from the phosphonation of an OH group on the parentcompound. A thorough discussion of prodrugs is provided in Higuchi etal., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. SymposiumSeries; Roche, et al. ed., Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987; Rautio etal., Prodrugs: Design and Clinical Applications, Nat. Rev. DrugDiscovery, 2008, 7, 255-270, and Hecker et al, Prodrugs of Phosphatesand Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of which areincorporated herein by reference.

Unless otherwise stated, all tautomeric forms of the compounds disclosedherein are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. The metabolite of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzyme cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds disclosedherein, including compounds produced by a process comprising contactinga compound disclosed herein with a mammal for a period of timesufficient to yield a metabolic product thereof.

Stereochemical definitions and conventions used herein generally followParker et al., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York and Eliel et al., “Stereochemistry ofOrganic Compounds”, John Wiley & Sons, Inc., New York, 1994. Thecompounds disclosed herein may contain asymmetric or chiral centers, andtherefore exist in different stereoisomeric forms. It is intended thatall stereoisomeric forms of the compounds disclosed herein, includingbut not limited to, diastereomers, enantiomers and atropisomers, as wellas mixtures thereof such as racemic mixtures, form part of the presentinvention. Many organic compounds exist in optically active forms, i.e.,they have the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L, or R andS, are used to denote the absolute configuration of the molecule aboutits chiral center(s). The prefixes d and l or (+) and (−) are employedto designate the sign of rotation of plane-polarized light by thecompound, with (−) or l meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The term “racemic mixture” or “racemate” refers to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.Some non-limiting examples of proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

A “pharmaceutically acceptable salt” refers to organic or inorganicsalts of a compound disclosed herein. The pharmaceutically acceptablesalt is well known in the art. For example, Berge et al., describe thepharmaceutically acceptable salt in detail in J. Pharmacol Sci, 1977,66: 1-19, which is incorporated herein by reference. Some non-limitingexamples of the pharmaceutically salt include salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,laurylsulfate, malate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate,valerate salts, and the like. Salts derived from appropriate basesinclude alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄salts. This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroilsoluble or dispersable products may be obtained by suchquaternization. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C₁₋₈ sulfonate or aryl sulfonate.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound disclosed herein. Some non-limiting examples ofthe solvents that form solvates include water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term“hydrate” refers to the complex where the solvent molecule is water.

The term “protecting group” or “Pg” refers to a substituent that iscommonly employed to block or protect a particular functionality whilereacting with other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound. Somenon-limiting examples of the suitable amino-protecting group includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Some non-limitingexamples of the suitable hydroxy-protecting group include acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality. Somenon-limiting examples of the common carboxy-protecting group include—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl,and the like. For a general description of protecting groups and theiruse, see Greene et al., Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991 and Kocienski et al., Protecting Groups,Thieme, Stuttgart, 2005.

It should be noted that the term of “inhibiting HCV viral protein”should be broadly understood, which comprises inhibiting the expressionlevel of HCV viral protein, inhibiting activity level of HCV viralprotein, viral assembly and egress level. The expression level of HCVprotein includes but not limited to translation level of the viralprotein, posttranslational modification level of the viral protein,replication level of genetic material in offsprings and so on.

Description of Compounds of the Invention

Disclosed herein are spiro ring compounds and pharmaceuticalformulations thereof, which are useful in inhibiting HCV infection,especially inhibiting the activity of the non-structural 5A (“NS5A”)protein.

In one aspect, provided herein are compounds having Formula (I) as shownbelow:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein:A is a single bond, alkylene, alkenylene, cycloalkylene,heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—, or—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶, or CR⁷R^(7a);X⁴ is (CR⁷R^(7a))_(n), —Y¹═Y²—, O, S or NR⁶;W is a carbocyclyl or heterocyclyl ring;each Y¹ and Y² is independently N or CR⁷;Z is —(CH₂)_(a)—, —CH═CH—, —N═CH—, —(CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or—(CH₂)_(a)—O—(CH₂)_(b);each c and d is independently 1 or 2;each a, b, n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2;each of Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each e and f is independently 0, 1, 2, 3 or 4;each of X and X′ is independently N or CR⁷;each of Y and Y′ is independently H, deuterium, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, a monovalent groupderived from α-amino acid or an optically isomer thereof, or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U— (CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;each Q⁴ and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O)₂—;each t is independently 0, 1, 2, 3 or 4;each k is independently 0, 1 or 2;each of R¹, R², R³ and R⁴ is independently H, deuterium, alkyl,heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; orR¹ and R², together with X—CH they are attached to, optionally form a3-8 membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; or R³and R⁴, together with X′—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle;each R⁵ is independently H, deuterium, hydroxy, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy,alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl, alkyl-OS(═O)_(r)—,alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)— or aminosulfonyl;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N-alkyl, R¹³S(═O)- alkyl,R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy,R¹³R^(13a)N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl,haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro,aralkyl, arylamino, heteroarylamino, arylalkylamino,heteroarylalkylamino, heteroaryloxy, heteroarylalky, arylalkoxy,heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy,heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl,alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy,heterocyclylalkylamino or aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, aliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl or carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N-alkyl, R¹³S(═O)- alkyl,R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy,R¹³R^(13a)N—C(═O)-alkoxy, aryl, heteroaryl, alkoxy, alkylamino, alkyl,haloalkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, mercapto, nitro,aralkyl, arylamino, heteroarylamino, arylalkylamino,heteroarylalkylamino, heteroaryloxy, heteroarylalkyl, arylalkoxy,heteroarylalkoxy, heterocyclyloxy, heterocyclylalkoxy,heterocyclylamino, alkylacyl, alkylacyloxy, alkoxyacyl, alkylsulfonyl,alkoxysulfonyl, alkylsulfinyl, alkylsulfonyloxy, alkylsulfinyloxy,heterocyclylalkylamino or aryloxy;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I,aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;each R8 and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl,alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)— or aminosulfonyl;each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl orcycloalkylalkyl;each R¹² is independently R^(13a)R¹³N—, —C(═O)R¹³, —C(═S)R¹³,—C(═O)—O—R¹³, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, alkyl, heteroalkyl,cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl;or R¹¹ and R¹² are optionally joined to form a 4-7 membered ring; andand each R¹³ and R^(13a) is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; withthe proviso that where R¹³ and R^(13a) are bonded to the same nitrogenatom, R¹³ and R^(13a), together with the nitrogen atom they are attachedto, optionally form a substituted or unsubstituted 3-8 membered ring,spiro bicyclic ring or fused bicyclic ring;wherein each of alkylene, alkenylene, cycloalkylene,heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—NR¹¹—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹²,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹CR^(9a))_(t)]_(k)—U—(CR⁹CR^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²,NR⁶, CR⁷R^(7a), CR⁷, —(CH₂)_(a)—, —CH═CH—, —N═CH—,—(CH₂)_(a)—N(R⁵)—(CH₂)_(b)—, —(CH₂)_(a)—O—(CH₂)_(b)—, R^(13a)R¹³N—,—C(═O)R¹³, —C(═S)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, alkyl-OC(═O)—,alkyl-C(═O)—, alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R^(13a)R¹³N-alkyl,R¹³S(═O)-alkyl, R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy,R¹³S(═O)-alkoxy, R¹³R^(13a)N—C(═O)-alkylamino, alkyl, heteroalkyl,carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,α-amino acid, C₅₋₁₂ fused bicycle, C₅₋₁₂ fused heterobicycle, C₅₋₁₂spiro bicycle, C₅₋₁₂ spiro heterobicycle, alkoxy, aliphatic,haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic,alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino,heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy,heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino andaryloxy is optionally substituted with one or more substituentsindependently selected from hydroxy, deuterium, amino, halo, cyano,aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl,alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O),carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—,alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—, hydroxy-substitutedalkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂— or carboxyl-substitutedalkoxy.

In some embodiments, W is a C₃₋₈ carbocyclyl or C₂₋₁₀ heterocyclyl ring.

In some embodiments,

wherein each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each X⁶ is independently CR⁷R^(7a), O, S or NR⁶;each Y¹ and Y² is independently N or CR⁷;each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each e and f is independently 0, 1, 2, 3 or 4;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocycyl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl,C₂₋₁₀ heterocycyl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl; andeach R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a) togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments,

wherein each Y¹ and Y² is independently N or CH;each X⁶ is independently CR⁷R^(7a), O, S, or NR⁶;each R^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F,Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro or C₁₋₆ alkylamino;R⁶ is H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(═O)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₈cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl; andeach of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments, wherein A is a single bond, C₁₋₆ alkylene, C₂₋₆alkenylene, C₃₋₈ cycloalkylene, C₂₋₁₀ heterocycloalkylene,—(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)— or—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶ or CR⁷R^(7a);

Q⁴ is —C(═O)—, —S(═O)— or —S(═O)₂—;

each e is independently 0, 1, 2, 3 or 4;each Y¹ and Y² is independently N or CR⁷;Z is —(CH₂)_(a), —CH═CH—, —N═CH—, —(CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or—(CH₂)_(a)—O—(CH₂)_(b)—;each c and d is independently 1 or 2;each a b n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2;each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;R⁶ is H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(O)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, R^(13a)R¹³N—C₁₋₆-alkyl, R¹³S(═O)—C₁₋₆-alkyl,R¹³R^(13a)N—C(═O)—C₁₋₆-alkyl, R^(13a)R¹³N—C₁₋₆-alkoxy,R¹³S(═O)—C₁₋₆-alkoxy, R¹³R¹³N—C(═O)—C₁₋₆-alkoxy, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl,mercapto, nitro, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₆₋₁₀ arylamino, C₁₋₉heteroarylamino or C₆₋₁₀ aryloxy;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring; andeach R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl.

In some embodiments, A is a single bond, —CH₂—, —(CH₂)₂—, —CH═CH—,—CH═CH—CH₂—, —N(R⁵)—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R⁵)—,—OC(═O)N(R⁵)—, —OC(═O)O—, —N(R⁵)C(═O)N(R⁵)—, —(R⁵)N—S(═O)₂—, —S(═O)₂—,—OS(═O)₂—, —(R⁵)N—S(═O)—, —S(═O)—, —OS(═O)—, or A is

A′ is

wherein, X¹ is O or S;

Y¹ is N or CH;

each e is independently 0, 1, 2 or 3;each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;each R⁶ is independently H, deuterium, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆alkylamino-C₁₋₆-alkyl, C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl;each R^(6a) is independently H, deuterium, hydroxy, amino, F, Cl, Br, I,cyano, oxo(═O), R^(13a)R¹³N—, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, mercapto or nitro; andeach R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring.

In some embodiments, wherein each of R¹, R², R³ and R⁴ is independentlyH, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ heterocyclyl, C₁₋₉ heteroaryl or C₆₋₁₀ aryl; or R¹ andR², together with X—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; or R³and R⁴, together with X′—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle.

In other embodiments, R¹ and R², together with X—CH they are attachedto, or R³ and R⁴, together with X′—CH they are attached to, optionallyform a 3-8 membered heterocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle.

In other embodiments, R¹, R² and Y—X—CH together form one of thefollowing monovalent groups:

wherein each R¹⁵ is independently H, deuterium, oxo(═O), F, Cl, Br, I,cyano, hydroxy, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino, C₁₋₃ alkylthio, C₆₋₁₀ arylamino, C₆₋₁₀ aryloxy, C₁₋₉heteroaryl, C₁₋₉ heteroaryloxy, C₁₋₉ heteroaryl-C₁₋₃-alkyl or C₂₋₁₀heterocyclyl;each R⁶ is independently H, deuterium, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₃ alkoxy-C₁₋₃-alkyl, C₁₋₃alkylamino-C₁₋₃-alkyl, C₁₋₃ alkylthio-C₁₋₃-alkyl, C₆₋₁₀ aryl-C₁₋₃-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; andeach n₁ and n₂ is independently 1, 2, 3 or 4.

In other embodiments, R³, R⁴ and Y′—X′—CH together form one of thefollowing monovalent groups:

wherein each R¹⁵ is independently H, deuterium, oxo(═O), F, Cl, Br, I,cyano, hydroxy, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino, C₁₋₃ alkylthio, C₆₋₁₀ arylamino, C₆₋₁₀ aryloxy, C₁₋₉heteroaryl, C₁₋₉ heteroaryloxy, C₁₋₉ heteroaryl-C₁₋₃-alkyl or C₂₋₁₀heterocyclyl;each R⁶ is independently H, deuterium, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₃ alkoxy-C₁₋₃-alkyl, C₁₋₃alkylamino-C₁₋₃-alkyl, C₁₋₃ alkylthio-C₁₋₃-alkyl, C₆₋₁₀ aryl-C₁₋₃-alkyl,C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; andeach n₁ and n₂ is independently 1, 2, 3 or 4.

In some embodiments, the compound may have formula (II):

wherein,

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4;each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each Y¹ and Y² is independently N or CR⁷;A is a single bond, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₃₋₈ cycloalkylene,C₂₋₁₀ heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p),—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(r)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

X¹ is O, S, NR⁶ or CR⁷R^(7a);

each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;each R^(5a) and R^(6a) is independently H, deuterium, oxo(═O), hydroxy,amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³C(═O) R¹³R¹³N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)— R³R^(13a)NS(═O)₂,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆aliphatic, C₂₋₆ heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀ cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl;each R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2; andeach of Y₄ and Y₄′ is independently a single bond, O, S, —(CH₂)_(n)—,—CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—, —CF₂—, —CHR^(5a)—, —CR^(5a)R^(6a),—CH₂S(═O)_(r), or —CH₂N(R⁶)—.

In some embodiments, the compound may have formula (II′):

wherein

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4;each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each X⁶ is independently CH₂, O, S or NR⁶;A is a single bond, C₁₋₆ alkylene, C₂₋₆ alkenylene, C₃₋₈ cycloalkylene,C₂₋₁₀ heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl;each R^(5a) and R^(6a) is independently H, deuterium, oxo(═O), hydroxy,amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy,C₁₋₆ alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆alkylamino, C₃₋₁₀ cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl;each of R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆aliphatic, C₂₋₆ heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀ cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl;each R8 and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each n and p is independently 0, 1, 2 or 3;each r is independently 0, 1 or 2; andeach of Y₄ and Y₄′ is independently a single bond, O, S, —(CH₂)_(n)—,—CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—, —CF₂—, —CR^(5a)R^(6a)—, CHR^(5a)—,—CH₂S(═O)_(r), or —CH₂N(R⁶)—.

In other embodiments, the compound may have formula (III):

In other embodiments, the compound may have formula (IV):

Wherein each of Q² and Q³ is independently O, S, C(═O), NR⁶, or CH₂.

In other embodiments, the compound may have formula (V):

wherein e is 1, 2, 3 or 4.

In other embodiments, the compound may have formula (III′):

In other embodiments, the compound may have formula (IV′):

wherein each of Q² and Q³ is independently O, S, C(═O), NR⁶, or CH₂.

In other embodiments, the compound may have formula (V′):

wherein e is 1, 2, 3 or 4.

In some embodiments, each of Y and Y′ is independently a monovalentgroup derived from an α-amino acid which is optionally substituted withone or more substituents independently selected from deuterium, F, Cl,Br, I, hydroxy or cyano.

In other embodiments, the α-amino acid is isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophane, valine, alanine,asparagine, aspartic acid, glutamic acid, glutamine, proline, serine,p-tyrosine, arginine, histidine, cysteine, glycine, sarcosine,N,N-dimethylglycine, homoserine, norvaline, norleucine, ornithine,homocysteine, homophenylalanine, phenylglycine, o-tyrosine, m-tyrosineor hydroxyproline.

In other embodiments, the α-amino acid is in the D configuration.

In other embodiments, the α-amino acid is in the L configuration.

In some embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹¹)— (CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)_(t)—C(═O)—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—C(═O)—O—R¹³.

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)_(t)—C(═O)—O—R¹³.

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹².

In other embodiments, each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—R¹², wherein R¹¹ and R¹², together withthe atom they are attached to, form a 4-7 membered ring.

In other embodiments, each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H,deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;

each R¹² is independently R^(13a)R¹³N—, —C(═O)R¹³, —C(═S)R¹³,—C(═O)—O—R¹³, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a)R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl;or R¹¹ and R¹², together with the atom they are attached to, form a 4-7membered ring;each R¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring;each t is independently 0, 1, 2, 3 or 4; andeach k is independently 0, 1 or 2.

In other embodiments, each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H,deuterium, methyl, ethyl, isopropyl, cyclohexyl, isobutyl or phenyl;

each R¹² is independently —C(═O)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),methyl, ethyl, propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl;or R¹¹ and R¹², together with the atom they are attached to, form a 4-7membered ring; andeach R¹³ and R^(13a) is independently H, deuterium, methyl, ethyl,propyl, phenyl, cyclohexyl, morpholinyl or piperidinyl.

In other embodiments, the compound may have formula (VI):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl; wherein each ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In other embodiments, the compound may have formula (VII):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₃hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl,propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl,piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C₁₋₉ heteroaryl;wherein each of C₁₋₃ hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl,tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl,morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyland C₁₋₉ heteroaryl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano.

In some embodiments, the compound may have formula (VIII):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;each n₂ is independently 1, 2, 3 or 4; andwherein each of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆heteroalkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (IX):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl;each n₁ is independently 1, 2, 3 or 4; andwherein each of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆heteroalkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (X):

wherein R^(5a) is H, deuterium, methyl, ethyl, F, Cl, Br or I;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isopropyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, methoxy, ethoxy, benzyl, tert-butoxy and tert-butyl isoptionally substituted with one or more substituents independentlyselected from deuterium, F, Cl, Br, hydroxy or cyano;wherein

wherein Bn is benzyl;

A is

A′ is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In other embodiments, the compound may have formula (XI):

wherein, each R^(5a) is independently H, deuterium, C₁₋₄ alkyl, F, Cl,Br or I;i is 1, 2, 3 or 4;each of Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CR⁷R^(7a))_(e);each of e and f is independently 0, 1, 2, 3 or 4;

Q⁴ is —C(═O)—, —S(═O)— or —S(═O)₂; X¹ is O, NR⁶ or CR⁷R^(7a);

each of Y¹ and Y² is independently N or CR⁷;each R⁶, R⁷ and R^(7a) is independently H, deuterium, C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₄ alkyl, C₆₋₁₀aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;each of R¹⁶ and R^(16a) is independently hydroxy, C₁₋₄ alkoxy, C₆₋₁₀aryloxy, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl;wherein each of C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl, C₃₋₈cycloalkyl and C₆₋₁₀ aryloxy is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano;

A is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In other embodiments, each R^(5a) is independently H, deuterium, methyl,ethyl, F, C, Br or I;

each R is independently H, deuterium, methyl, ethyl, isopropyl, phenylor cyclohexyl;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isopropyl, isobutyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy andtert-butyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano.

In some embodiments, the compound may have formula (X′):

wherein R^(5a) is independently H, deuterium, methyl, ethyl, F, Cl, Bror I;each of Q¹ and Q² is independently CH₂, C(═O), CF₂, O, NR⁶ or S;

X⁶ is O, S, NH or CH₂;

R⁶ is H, deuterium, methyl, ethyl, isopropyl, phenyl or cyclohexyl;each of R¹⁴ and R^(14a) is independently methyl, ethyl, phenyl,cyclohexyl, 1-methyl propyl, isobutyl, isopropyl or tert-butyl;each of R¹⁶ and R^(16a) is independently hydroxy, methoxy, ethoxy,phenoxy,

or tert-butoxy;wherein each of methyl, ethyl, phenyl, cyclohexyl, 1-methyl propyl,isopropyl, isobutyl, methoxy, ethoxy, phenoxy, tert-butoxy andtert-butyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano;

A is

A′ is

wherein

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

In some embodiments, non-limiting examples of compounds disclosedherein, or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, or a pharmaceutically acceptable salt thereof, areshown in the following:

Provided herein includes the use of a compound disclosed herein (Inpresent disclosure, “a compound disclosed herein” comprises a compoundof formula (I), a stereoisomer, a geometric isomer, a tautomer, anN-oxide, a hydrate, a solvate and a pharmaceutically acceptable saltthereof), in the manufacture of a medicament for the treatment eitheracutely or chronically of HCV infection in a patient, including thosedescribed herein. Also provided herein is the use of the compound in themanufacture of an anti-HCV medicament. Provided herein is the use of thecompound disclosed herein, in the manufacture of a medicament toattenuate, prevent, manage or treat HCV-mediated disease, especiallyHCV's NS5A protein. Also provided herein is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) in association with at least one pharmaceutically acceptablecarrier, adjuvant or diluent.

In certain embodiments, the salt is a pharmaceutically acceptable salt.The phrase “pharmaceutically acceptable” refers to that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a Formulation and/or the mammal beingtreated therewith. Persons skilled in the art can choose the“pharmaceutically acceptable” substance or composition specificallyaccording to other components and the object being treated with (such asman).

The compounds disclosed herein also include salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof formula (I) and/or for separating enantiomers of compounds of formula(I).

If the compound disclosed herein is a base, the desired salt may beprepared by any suitable method available in the art, for example,treatment of the free base with an inorganic acid, such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like. Or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, such asglucuronic acid or galacturonic acid; an alpha hydroxy acid, such ascitric acid or tartaric acid; an amino acid, such as aspartic acid orglutamic acid; an aromatic acid, such as benzoic acid or cinnamic acid;a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,and the like.

If the compound disclosed herein is an acid, the desired salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide or alkaline earth metalhydroxide, and the like. Some non-limiting examples of suitable saltsinclude organic salts derived from amino acids, such as glycine andarginine, ammonia, such as primary, secondary and tertiary amines, andcyclic amines, such as piperidine, morpholine and piperazine, andinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, lithium, and the like.

Composition, Formulations and Administration of Compounds of theInvention

The pharmaceutical composition disclosed herein comprises any one of thecompounds in the present disclosure. The pharmaceutical compositionfurther comprises a pharmaceutically acceptable carrier, excipient,diluent, adjuvant, vehicle or a combination thereof. And thepharmaceutical composition can be used for treating HCV infection or aHCV disorder, especially it is effective as inhibitor of thenon-structural 5A (NS5A) protein of HCV.

The pharmaceutical composition disclosed herein further comprises anadditional anti-HCV agent. The anti-HCV agent refers to any known agentsfor anti-HCV and they are different from the compounds disclosed herein.For example, the anti-HCV agent is interferon, ribavirin, IL-2, IL-6,IL-12, a compound that enhances the development of a type 1 helper Tcell response, interfering RNA, anti-sense RNA, imiquimod, aninosine-5′-monophosphate dehydrogenase inhibitor, amantadine,rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™),boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir,vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172,vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239,PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805,PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625,ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136,IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189,IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796,HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072,PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667,AZD-2795, TMC647055 or a combination thereof. The interferon isinterferon α-2b, pegylated interferon α, interferon α-2a, pegylatedinterferon α-2a, consensus interferon-α, interferon γ or a combinationthereof. The pharmaceutical composition disclosed herein furthercomprises at least one HCV inhibitor. In some embodiments, the HCVinhibitor inhibits at least one of HCV replication process and HCV viralprotein function. In some embodiments, the HCV replication process is awhole viral cycle consisting of HCV entry, uncoating, translation,replication, assembly and egress. In some embodiments, the HCV viralprotein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B, or aninternal ribosome entry site (IRES) or inosine-5′-monophosphatedehydrogenase (IMPDH) required in HCV viral replication.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “therapeutically effective amount” refers to thetotal amount of each active component that is sufficient to show ameaningful patient benefit (e.g., a reduction in viral load). Whenapplied to individual active ingredient, administered alone, the termrefers to that ingredient alone. When applied to a combination, the termrefers to combined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially, orsimultaneously. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof, are as described above. The carrier(s),diluents(s), or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to recipient thereof. In accordance with another aspect ofthe present disclosure there is also provided a process for thepreparation of a pharmaceutical formulation including admixing acompound of formula (I) or a pharmaceutically acceptable salt thereof,with one or more pharmaceutically acceptable carriers, diluents orexcipients. The term “pharmaceutically acceptable” refers to thosecompounds, materials, composition and/or dosage forms which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of patients without excessive toxicity, irritation, allergicresponse, or other problem or complication commensurate with areasonable benefit/risk ratio, and are effective for their intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment of HCVmediated disease. Typically, the pharmaceutical compositions of thisdisclosure will be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight and condition of the patient. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Treatment may be initiated with small dosages substantiallyless than the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. In general, the compound is most desirablyadministered at a concentration level that will generally affordantivirally effective results without causing any harmful or deleteriousside effects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more additionaltherapeutic or prophylactic agent, both the compound and the additionalagent are usually present at dosage levels of between about 10 to 150%,and more preferably between about 10 to 80% of the dosage normallyadministered in a monotherapy regimen. Pharmaceutical formulations maybe adapted for administration by any appropriate route, for example bythe oral (including buccal or sublingual), rectal, nasal, topical(including buccal, sublingual or transdermal), vaginal or parenteral(including subcutaneous, intracutaneous, intramuscular, intra-articular,intrasynovial, intrasternal, intrathecal, intralesional, intravenous, orintradermal injections or infusions) route. Such formulations may beprepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s). Oral administration or administration by injection ispreferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solution or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose, 3-lactose, corn sweetener, natural gum and syntheticresin such as Arabic gum, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluents or base as described above, and optionally,with a binder such as carboxymethylcellulose, an alginate, gelatin orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadiamucilage or solution of cellulosic or polymeric materialsand forcing through a screen. As an alternative to granulation, thepowder mixture can be run through the tablet machine and the result isimperfectly formed slugs broken into granules. The granules can belubricated to prevent sticking to the tablet forming dies by means ofthe addition of stearic acid, a stearate salt, talc or mineral oil. Thelubricated mixture is then compressed into tablets. The compounds of thepresent disclosure can also be combined with a free flowing inertcarrier and compressed into tablets directly without going through thegranulating or slugging steps. A clear or opaque protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial, and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additives such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carrier to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid,poly(s-caprolactone), polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked oramphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti oxidants, buffers, bacteriostats, and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

Use of the Compounds and Compositions of the Invention

Provided herein is use of the compound or the pharmaceutical compositionin the manufacture of a medicament for inhibiting at least one of HCVreplication process and HCV viral protein function. In some embodiments,the HCV replication process is a whole viral cycle consisting of HCVentry, uncoating, translation, replication, assembly and egress. In someembodiments, the HCV viral protein is metalloproteinase, NS2, NS3, NS4A,NS4B, NS5A or NS5B, or an internal ribosome entry site (IRES) orinosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication. And any one of the compounds or the pharmaceuticalcompositions disclosed herein can be used for treating HCV infection ora HCV disorder, especially it is effective as inhibitor of thenon-structural 5A (NS5A) protein of HCV.

Also provided herein is a method, which comprises the compound or thepharmaceutical composition disclosed herein, further comprisingadministering to the patient additional anti-HCV agents (combinationtherapy), wherein the anti-HCV agent is interferon, ribavirin, IL-2,IL-6, IL-12, a compound that enhances the development of a type 1 helperT cell response, interfering RNA, anti-sense RNA, imiquimod, aninosine-5′-monophosphate dehydrogenase inhibitor, amantadine,rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™),boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir,vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172,vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239,PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805,PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625,ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136,IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189,IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796,HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072,PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667,AZD-2795, TMC647055 or a combination thereof; and the interferon isinterferon α-2b, pegylated interferon α, interferon α-2a, pegylatedinterferon α-2a, consensus interferon-α, or interferon γ.

The treatment method that includes administering a compound orcomposition disclosed herein can further include administering to thepatient an additional anti-HCV agent, wherein the additional anti-HCVdrug is administered together with a compound or composition disclosedherein as a single dosage form or separately from the compound orcomposition as part of a multiple dosage form. The additional anti-HCVagent may be administered at the same time as a compound disclosedherein or at a different time. In the latter case, administration may bestaggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1week, 2 weeks, 3 weeks, 1 month or 2 months.

In certain embodiments disclosed herein, an “effective amount” or“effective dose” of the compound or pharmaceutically acceptablecomposition is that amount effective for treating or lessening theseverity of one or more of the aforementioned disorders. The compoundsand compositions, according to the method disclosed herein, may beadministered using any amount and any route of administration effectivefor treating or lessening the severity of the disorder or disease. Theexact amount required will vary from subject to subject, depending onthe species, age, and general condition of the subject, the severity ofthe infection, the particular agent, its mode of administration, and thelike. A compound or composition can also be administered with one ormore other therapeutic agents, as discussed above.

General Synthetic Procedures

Generally, the compounds disclosed herein may be prepared by methodsdescribed herein, wherein the substituents are as defined for formula(I), above, except where further noted. The following non-limitingschemes and examples are presented to further exemplify the invention.

Persons skilled in the art will recognize that the chemical reactionsdescribed herein may be readily adapted to prepare a number of othercompounds disclosed herein, and alternative methods for preparing thecompounds disclosed herein are deemed to be within the scope disclosedherein. For example, the synthesis of non-exemplified compoundsaccording to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds disclosed herein.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, and were used withoutfurther purification unless otherwise indicated. Common solvents werepurchased from commercial suppliers such as Shantou XiLong ChemicalFactory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., GuangzhouReagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., QingdaoTenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous THF, dioxane, toluene and ether were obtained by refluxing thesolvent with sodium. Anhydrous CH₂Cl₂ and CHCl₃ were obtained byrefluxing the solvent with CaH₂. EtOAc, PE, hexane, DMAC and DMF weretreated with anhydrous Na₂SO₄ prior to use.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silicagel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. ¹HNMR spectra were obtained as CDCl₃, d₆-DMSO, CD₃OD or d₆-acetonesolutions (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm)as the reference standard. When peak multiplicities are reported, thefollowing abbreviations are used: s (singlet), d (doublet), t (triplet),q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, are reported inHertz (Hz).

Low-resolution mass spectral (MS) data were also determined on anAgilent 6320 series LC-MS spectrometer equipped with G1312A binarypumps, a G1316A TCC (Temperature Control of Column, maintained at 30°C.), a G1329A autosampler and a G1315B DAD detector were used in theanalysis. An ESI source was used on the LC-MS spectrometer.

Low-resolution mass spectral (MS) data were also determined on anAgilent 6120 series LC-MS spectrometer equipped with G1311A Quaternarypump, a G1316A TCC (Temperature Control of Column, maintained at 30°C.), a G1329A autosampler and a G1315D DAD detector were used in theanalysis. An ESI source was used on the LC-MS spectrometer.

Both LC-MS spectrometers were equipped with an Agilent Zorbax SB—C18,2.1×30 mm, 5 μm column. Injection volume was decided by the sampleconcentration. The flow rate was 0.6 mL/min. The HPLC peaks wererecorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid inultrapure water (phase B). The gradient condition is shown in Table 1:

TABLE 1 A (CH₃CN, B (H₂O, Time (min) 0.1% HCOOH) 0.1% HCOOH) 0-3 5-10095-0 3-6 100  0  6-6.1 100-5    0-95 6.1-8   5 95

Purities of compounds were also assessed by Agilent 1100 Series highperformance liquid chromatography (HPLC) with UV detection at 210 nm and254 nm (Zorbax SB—C18, 2.1×30 mm, 4 micron, 10 min, 0.6 mL/min flowrate, 5 to 95% (0.1% formic acid in CH₃CN) in (0.1% formic acid in H₂O).Column was operated at 40° C.

The following abbreviations are used throughout the specification:

HOAc acetic acidMeCN, CH₃CN acetonitrileNH₃ ammoniaNH₄Cl ammonium chlorideBBr₃ boron tribromideBSA bovine serum albuminBr₂ bromineBOC, Boc tert-butyloxycarbonylCbz benzylcarboxyCs₂CO₃ cesium carbonateCHCl₃ chloroformCDCl₃ chloroform deuterated

CDI 1,1′-Carbonyldiimidazole

Cu copperCuI copper (I) iodideEt₂O diethyl etherDMF dimethylformamideDMAP 4-dimethylaminopyridineDMSO dimethylsulfoxideEDC, EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideDppa diphenylphosphoryl azideEtOAc, EA ethyl acetateFmoc fluorenylmethyloxycarbonylHBr hydrobromic acidHCl hydrochloric acidHOAt, HOAT 1-hydroxy-7-azabenzotriazoleHOBT 1-hydroxybenzotriazole hydrateH₂ hydrogenH₂O₂ hydrogen peroxideFe ironLDA lithium diisopropylamideMCPBA meta-chloroperbenzoic acidMgSO₄ magnesium sulfateMeOH, CH₃OH methanolMeI methyl iodideCH₂Cl₂, DCM methylene chloride

NMP N-methylpyrrolidinone

mL, m milliliterN₂ nitrogenPd/C palladium on carbonPE petroleum ether (60-90° C.)PBS phosphate buffered salinePOCl₃ phosphorous oxychloridePd(PPh₃)₄ palladium tetrakis triphenylphosphinePd(dppf)Cl₂ 1,1-bis(diphenylphosphino)ferrocene palladium chlorideK₂CO₃ potassium carbonateKOH potassium hydroxideRT, rt room temperatureRt retention timeNaHCO₃ sodium bicarbonateNaBH₄ sodium borohydrideNaBH₃CN sodium cyanoborohydrideNaOtBu sodium tert-butoxideNaOH sodium hydroxideNaClO₂ sodium chloriteNaCl sodium chlorideNaH₂PO₄ sodium dihydric phosphateNaH sodium hydrideNaI sodium iodideNa₂SO₄ sodium sulfateTBTU O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborateTHF tetrahydrofuranEt₃N, TEA triethylamineTFA trifluoroacetic acidP(t-bu)₃ tri(tert-butyl)phosphine

NBS N-bromosuccinimide

TBAI tetrabutylammonium iodideH₂O waterTEAF formic acid triethylamine complex 5:2PPA polyphosphoric acidTf₂O Trifluoromethanesulfonic anhydrideHCl.EA a solution of HCl in ethyl acetate

DIPEA N,N-diisopropylethylamine

DME 1,2-dimethoxyethaneHATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

NIS N-iodosuccinimide

TFAA trifluoroaceticanhydrideSEMCl2—(Trimethylsilyl)ethoxymethyl chlorideDess-Martin (Dess-Martin periodinane)(1,1,1-Triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-onep-TSA(TsOH) p-toluenesulfonic acidTMSA Trimethyl silyl acetyleneMeldrum's acid 2,2-Dimethyl-1,3-dioxane-4,6-dioneBAST Bis(2-methoxyethyl)aminosulphurtrifluoride Deoxo-fluorSbCL₃ antimony trichlorideSmCl₃ samarium chlorideLiHMDS lithium hexamethyldisilazideTMSCl trimethyl chlorosilane

PhNTf₂ N,N-Bis(trifluoromethylsulfonyl)aniline

TBDMSOTf tert-butyldimethylsilyl triflateEt₂NSF₃ diethylaminosulfur trifluorideMTBE methyl tert-butyl etherLiN(SiMe₃)₂ Lithium bis(trimethylsilyl)amidePPh₃MeBr Methyltriphenylphosphonium bromideLawesson's Reagent 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane2,4-disulfideTEBAC benzyltriethylammonium chlorideI₂ iodineDAST Diethylaminosulfur trifluorideIPA isopropanolTCCA trichloroisocyanuric acidTEMPO 2,2,6,6-tetramethylpiperidinooxyIMPDH Inosine monophosphate dehydrogenaseIRES Internal ribosome entry site

Compound 22 can be prepared by the process illustrated in Scheme 1.Wherein each X⁵ is F, Cl, Br or I and each of Y², w, R^(5a), f, Y₄′, Y¹,Y₄, R^(6a), R¹⁴, R^(14a), R¹⁶ and R^(16a) is as defined herein. Pg is aamino-protecting group such as Boc, Fmoc or Cbz. Compound 1 can undergocyclization to give compound 2 in the presence of a base. Compound 2 canreact with a reductant to give compound 3. Compound 3 can be transformedto compound 4 by reacting with NIS. The methyl group in compound 4 canthen be removed in the presence of boron tribromide to provide compound5. Compound 5 can react with trifluoromethanesulfonic anhydride toafford compound 6 in the presence of a base catalyst. Condensation ofcompound 7 with compound 8 can give compound 9. Then compound 9 canundergo cyclization to give compound 10 at elevated temperature in thepresence of ammonium acetate. The protecting group Pg in compound 10 canbe removed to provide compound 11. Compound 11 can then condense with aamino acid to afford compound 12. Compound 12 can react withbis(pinacolato)diboron in the presence of a Pd catalyst to affordcompound 13. Coupling reaction of compound 13 with compound 6 in thepresence of a Pd catalyst can give compound 14. Compound 15 can beconverted to compound 16 by base catalysis. Compound 16 can be convertedto compound 17 in the presence of CDI and ammonium hydroxide.Condensation of compound 17 with compound 18 can give compound 19.Compound 19 can be cyclized in the presence of a base to form compound20. Reaction of compound 20 with bis(pinacolato)diboron can affordcompound 21 in the presence of a Pd catalyst. Coupling reaction ofcompound 21 with compound 14 in the presence of a Pd catalyst can givecompound 22.

Compound 30 can be prepared by the process illustrated in Scheme 2.Wherein each X⁵ is F, Cl, Br or I and each of Y², w, R^(5a), f, Y₄′, Y¹,Y₄, R^(6a), R¹⁴, R^(14a), R¹⁶ and R^(16a) is as defined herein. Pg is aamino-protecting group such as Boc, Fmoc or Cbz. Compound 23 can beconverted to compound 24 by reacting with ethyl potassium malonate inthe presence of CDI/MgCl₂. Reaction of compound 24 with compound 25 canafford compound 26 by acid catalysis. The protecting group Pg incompound 26 can be removed to provide compound 27. Compound 27 can thenbe condensed with a amino acid to afford compound 28. Compound 28 canfurther react with bis(pinacolato)diboron in the presence of a Pdcatalyst to afford compound 29. Coupling reaction of compound 29 withcompound 14 in the presence of a Pd catalyst can give compound 30.

Compound 43 can be prepared by the process illustrated in Scheme 3.Wherein each X⁵ is F, Cl, Br or I and each of Y², w, R^(5a), f, Y₄′, Y¹,Y₄, R^(6a), R⁹, R^(9a), R¹⁴, R^(14a), R¹⁶ and R^(16a) is as definedherein. Pg is a amino-protecting group such as Boc, Fmoc or Cbz.Compound 31 can be converted to compound 32 by reacting with diethylmalonate by base catalysis. Compound 32 can be converted to compound 33in the presence of LiCl and water. Compound 33 can give compound 34 inthe presence of a base by alkylation. Compound 34 can afford compound 35by base catalysis. Compound 35 can be converted to compound 36 in thepresence of a base and DPPA. Condensation of compound 36 with compound23 can give compound 37. Compound 37 can react with a reductant to givecompound 38. Then compound 38 can undergo cyclization to give compound39 in the presence of acetic acid. The protecting group Pg in compound39 can be removed to provide compound 40. Compound 40 can then becondensed with an amino acid to afford compound 41. Compound 41 canfurther react with bis(pinacolato)diboron in the presence of a Pdcatalyst to afford compound 42. Coupling reaction of compound 42 withcompound 14 in the presence of a Pd catalyst can give compound 43.

Compound 53 can be synthesized through the procedure depicted in Scheme4. Wherein each X⁵ is independently F, Cl, Br or I and each of w, Y₄′,Y₄, Y¹, Y², R^(5a), R^(6a), f, R¹⁴, R^(14a), R¹⁶ and R^(16a) is asdefined herein, and Pg is an amino-protecting group such as Boc, Fmoc orCbz. Compound 44 can be transformed to compound 45 by reacting withsodium sulfite. Compound 45 can be converted to compound 46 in thepresence of thionyl chloride and ammonium hydroxide. Reduction ofcompound 46 with a reducing agent such as HI can afford compound 47.Reaction of compound 47 with compound 48 can form compound 49 in thepresence of a base. The protecting group Pg in compound 49 can beremoved to afford compound 50. Compound 50 can then be condensed with anamino acid to provide compound 51. Reaction of compound 51 withbis(pinacolato)diboron can afford compound 52 by Pd catalysis. Couplingreaction of compound 52 with compound 14 in the presence of a Pdcatalyst can give compound 53.

Compound 64 can be prepared by the process illustrated in Scheme 5.Wherein each of Y₄, Y₄′, w, R^(5a), f, Y², R¹⁴, R^(14a), R¹⁶ and R^(16a)is as defined herein, and Pg is an amino-protecting group such as Boc,Fmoc or Cbz. Compound 7 can react with a reductant such as diborane togive compound 54. Compound 54 can be oxidized to give compound 55 withan oxidant such as Dess-Matin agent. Compound 55 can be cyclized in thepresence of ammonium hydroxide and glyoxal to form compound 56. Compound56 can be transformed to diiodo compound 57 by reacting with NIS. One ofthe iodine atoms of the diiodo compound 57 can then be removed in thepresence of sodium sulfite to provide compound 58. The protecting groupPg in compound 58 can be removed to provide compound 59. Compound 59 canfurther condense with an amino acid to afford compound 60. Reaction ofcompound 60 with TMSA can afford compound 61 by Pd catalysis. Compound61 can give compound 62 by removing TMS in the presence of a base.Coupling reaction of compound 62 with compound 63 in the presence of aPd catalyst can give compound 64.

Compound 70 can be synthesized through the procedure depicted in Scheme6. Wherein each X⁵ is independently F, Cl, Br or I and each of w, Y₄′,Y₄, Y¹, R^(5a), R^(6a), f, R¹⁴, R^(14a), R¹⁶ and R^(16a) is as definedherein, and Pg is an amino-protecting group such as Boc, Fmoc or Cbz.Compound 65 can be transformed to compound 67 by reacting with compound66 in the presence of an acid. Compound 67 can further react withcompound 13 in the presence of a Pd catalyst to afford compound 68.Coupling reaction of compound 68 with compound 69 in the presence of aPd catalyst can give compound 70.

Compound 73 can be prepared by the process illustrated in Scheme 7.Wherein each of Y₄, Y₄′, Y², w, R^(5a), f, R¹⁴, R^(14a), R¹⁶ and R^(16a)is as defined herein. Reaction of compound 63 withbis(pinacolato)diboron can afford compound 71 by Pd catalysis. Couplingreaction of compound 71 with compound 72 in the presence of a Pdcatalyst can give compound 73.

Compound 79 can be prepared by the process illustrated in Scheme 8.Wherein each of Y₄, Y₄′, X², Y², w, R^(5a), R¹⁴, R^(14a), R¹⁶ andR^(16a) is as defined herein. Coupling reaction of compound 63 withcompound 74 in the presence of a Pd catalyst can give compound 75.Compound 75 can react with trifluoromethanesulfonic anhydride to affordcompound 76 by base catalysis. Reaction of compound 76 withbis(pinacolato)diboron can afford compound 77 by a Pd catalysis.Coupling reaction of compound 77 with compound 78 in the presence of aPd catalyst can give compound 79.

Compound 89 can be synthesized through the procedure depicted in Scheme9. Wherein each X is independently F, Cl, Br or I and each of Y₄, Y₄′,Y², Y¹, w, R^(5a), R^(6a), f, R¹⁴, R^(14a), R¹⁶ and R^(16a) is asdefined herein. Brominating compound 80 with NBS can give compound 81.Compound 81 can be converted to compound 82 by reacting with diethylmalonate by base catalysis. Compound 82 can be converted to compound 83in the presence of NaCl. Compound 84 can be formed via compound 83 byhydrolysis in base system. Compound 84 can react with acetyl chloride toafford compound 85 in the presence of aluminium chloride. Compound 85can undergo cyclization to give compound 86 in the presence of a base.Compound 86 can react with a reductant to give compound 87. Couplingreaction of compound 87 with compound 13 can afford compound 88 by Pdcatalysis. Coupling reaction of compound 88 with compound 52 in thepresence of a Pd catalyst can give compound 89.

EXAMPLES Example 1

Step 1) the Preparation of Compound 1-2

A mixture of aluminium chloride (90.0 g, 676 mmol) and sodium chloride(25.0 g, 432 mmol) was stirred at 150° C. until the solid was melted,and then compound 1-1 (20.0 g, 135 mmol) was added slowly. At the end ofthe addition, the mixture was stirred at 200° C. for 1.0 hr. After thereaction was completed, the mixture was cooled to rt and poured slowlyinto ice-water (500 mL), then filtered to get a gray solid which waspurified by beating in methanol to give the title compound 1-2 (19.0 g,95%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 149.5 [M+H]⁺; and

1HNMR (400 MHz, CDCl₃) δ (ppm): 7.41-7.38 (m, 1H), 7.24-7.19 (m, 1H),6.80-6.79, 6.78-6.77 (d, d, 1H, J=4.0 Hz), 5.46 (br, 1H), 3.06-3.03 (m,2H), 2.69-2.66 (m, 2H).

Step 2) the Preparation of Compound 1-3

To a mixture of compound 1-2 (5.0 g, 33.7 mmol) and K₂CO₃ (23.4 g, 168.5mmol) in acetone (50.0 mL) was added iodomethane (3.15 mL, 50.55 mmol).At the end of the addition, the mixture was stirred at 60° C. for 5.0hrs. After the reaction was completed, the mixture was concentrated invacuo. The residue was dissolved in EtOAc (150 mL) and water (150 mL),and then filtered through a celite pad. The aqueous layer was extractedwith EtOAc (150 mL×2). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as a yellow solid (2.5 g, 45%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 163.5 [M+H]⁺; and

¹HNMR (400 MHz, CDCl₃) δ (ppm): 7.51-7.48 (m, 1H), 7.30-7.26 (m, 1H),6.91-6.87 (m, 1H), 3.90 (s, 3H), 3.08-3.05 (m, 2H), 2.70-2.67 (m, 2H).

Step 3) the Preparation of Compound 1-4

To a suspension of potassium tert-butanolate (3.5 g, 31.19 mmol) intoluene (40.0 mL) was added a solution of 4-methoxy-1-indanone (2.0 g,12.34 mmol) and 1,4-dibromobutane (3.2 g, 14.96 mmol) in toluene (20.0mL) dropwise at 0° C. At the end of the addition, the mixture wasstirred at 90° C. for 5.0 hrs. After the reaction was completed, themixture was quenched with ice-water (100 mL). The aqueous phase wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/DCM(v/v)=3/1) to give the title compound 1-4 as yellow slurry (2.0 g, 75%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 217.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.36-7.31 (m, 2H), 7.03-7.01 (m, 1H),3.89 (s, 3H), 2.94 (s, 2H), 2.01-1.90 (m, 4H), 1.81-1.76 (m, 2H),1.62-1.56 (m, 2H).

Step 4) the Preparation of Compound 1-5

To a suspension of compound 1-4 (2.0 g, 9.25 mmol) and triethylsilane(7.4 mL, 46.33 mmol) was added TFA (20.0 mL, 26.93 mmol) dropwise at 0°C. At the end of the addition, the mixture was stirred at 40° C. for 24hrs. After the reaction was completed, the mixture was concentrated invacuo. The residue was dissolved in DCM (100 mL). The resulting mixturewas washed with Na₂CO₃ aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/DCM (v/v)=15/1) to give the title compound 1-5as colorless oil (1.59 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 203.14 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.13-7.10 (m, 1H), 6.81-6.80 (m, 1H),6.67-6.65 (m, 1H), 3.83 (s, 1H), 2.85 (s, 2H), 2.80 (s, 2H), 1.72-1.57(m, 8H).

Step 5) the Preparation of Compound 1-6

To a mixture of compound 1-5 (14.1 g, 69.8 mmol) and NIS (17.2 g, 76.8mmol) in MeCN (200 mL) was added CF₃COOH (0.5 mL, 6.98 mmol) dropwise at0° C. At the end of the addition, the mixture was stirred at 45° C.overnight. After the reaction was completed, the mixture wasconcentrated in vacuo, then 100 mL of water was added, and the mixturewas extracted with EtOAc (100 mL×3). The combined organic layers werewashed with saturated sodium sulfite aqueous solution (50 mL×2) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/DCM(v/v)=20/1) to give the title compound (19.7 g, 86%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 329.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.45 (d, 1H), 6.43 (d, 1H), 3.77 (s,3H), 2.90 (s, 2H), 2.81 (s, 2H), 1.73-1.69 (m, 4H), 1.63-1.59 (m, 4H).

Step 6) the Preparation of Compound 1-7

To a solution of compound 1-6 (19.6 g, 59.7 mmol) in DCM (15.0 mL) wasadded boron tribromide (74.7 g, 298.8 mmol) dropwise at −78° C. At theend of the addition, the mixture was stirred at −78° C. for 10 mins, andthen stirred at rt for another 1.0 hr. After the reaction was completed,the mixture was quenched with ice-water (100 mL). The aqueous layer wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/DCM(v/v)=20/1) to give the title compound (17.25 g, 92%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 315.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.36 (d, 1H), 6.41 (d, 1H), 4.91 (s,1H), 2.89 (s, 2H), 2.82 (s, 2H), 1.73-1.69 (m, 4H), 1.67-1.63 (m, 4H).

Step 7) the Preparation of Compound 1-8

To a solution of compound 1-7 (5.0 g, 15.92 mmol) in DCM (50.0 mL) wasadded pyridine (6.5 mL, 79.62 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (8.0 mL,47.77 mmol) was added, and then the mixture was stirred at rt for 1.0hr. After the reaction was completed, the mixture was quenched withice-water (100 mL). The aqueous layer was extracted with DCM (60 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=20/1) to give the title compoundas yellow oil (5.98 g, 84.2%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.57 (d, 1H), 6.79 (d, 1H), 3.07 (s,2H), 2.88 (s, 2H), 1.75-1.72 (m, 4H), 1.65-1.63 (m, 4H).

Step 8) the Preparation of Compound 1-10

A mixture of compound 1-9 (25.0 g, 125.6 mmol), NBS (24.5 g, 138.2 mmol)and p-TSA (3.4 g, 20.9 mmol) was stirred at 100° C. under N₂ for 2.0hrs. After the reaction was completed, the mixture was cooled to rt anddiluted with DCM (200 mL). The resulting mixture was washed with water(50 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=15/1) to give the title compound (25.0 g, 72%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 276.8 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.93 (d, 1H), 7.78 (d, 1H), 4.93 (s,2H).

Step 9) the Preparation of Compound 1-11

To a solution of compound 1-10 (30 g, 107.9 mmol) and compound 1-10-2(25.6 g, 118.7 mmol) in DCM (250 mL) was added DIPEA (21.4 mL, 129.5mmol) dropwise at 0° C. At the end of the addition, the mixture wasstirred at rt for 3.0 hrs. After the reaction was completed, thereaction was quenched with ice water (100 mL), and the aqueous layer wasextracted with EtOAc (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound (40 g, 91%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 412.7 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H),5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m, 1H), 3.48-3.38 (m,1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85 (m, 1H), 1.45 (d,9H).

Step 10) the Preparation of Compound 1-12

A suspension of compound 1-11 (15.0 g, 36.4 mmol) and ammonium acetate(42.0 g, 54.6 mmol) in xylene (150 mL) was stirred at 120° C. for 5.0hrs. After the reaction was completed, the mixture was cooled to rt andthe reaction was quenched with water (100 mL). The resulting mixture wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a white solid (12.1 g, 85%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 392.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H),7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m,1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85(m, 1H), 1.45 (d, 9H).

Step 11) the Preparation of Compound 1-13

To a solution of compound 1-12 (10.0 g, 25.5 mmol) in EtOAc (50.0 mL)was added a solution of HCl in EtOAc (60.0 mL, 4 M) dropwise, and themixture was stirred at rt for 8.0 hrs. After the reaction was completed,the mixture was concentrated in vacuo and EtOAc (30 mL) was added. Theresulting mixture was stirred and pulped, and then filtered to give thetitle compound as a pale yellow solid (8.0 g, 86.2%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 292.6 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H),7.21-7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m,1H), 3.49-3.39 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85(m, 1H).

Step 12) the Preparation of Compound 1-14

To a solution of compound 1-13 (7.03 g, 19.26 mmol), compound 1-13-2(5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) wasadded DIPEA (21 mL, 127 mmol) dropwise at 0° C., and the mixture wasstirred at rt for 3.0 hrs. After the reaction was completed, 100 mL ofwater was added to the mixture, and the aqueous layer was extracted withDCM (100 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound as a solid (7.6 g, 88%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 450.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H),7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m,1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H),2.34-2.22 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88-0.86 (d,6H).

Step 13) the Preparation of Compound 1-15

To a mixture of compound 1-14 (5.0 g, 11.13 mmol), compound 1-14-2 (4.3g, 16.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.91 g, 1.11 mmol) and KOAc (3.3 g,33.4 mmol) was added DMF (50.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was cooled to rt and diluted with EtOAc (200 mL). The resultingmixture was filtered through a celite pad. The filtrate was washed withwater (100 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (3.95g, 71.4%). The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H),7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m,1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H),2.34-2.22 (m, 1H), 2.21-1.95 (m, 5H), 1.45-1.32 (m, 12H), 1.04-1.02 (m,1H), 0.88-0.86 (d, 6H).

Step 14) the Preparation of Compound 1-16

To a mixture of compound 1-8 (3.56 g, 7.98 mmol), compound 1-15 (3.3 g,6.65 mmol), Pd(PPh₃)₄ (768 mg, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9 mmol)were added DME (50.0 mL) and H₂O (10.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 3.0 hrs. After the reaction wascompleted, DME was removed. The residue was dissolved in EtOAc (150 mL),and washed with water (50 mL×3) and brine, dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=100/1) to give the title compound as abeige solid (3.66 g, 80%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.84-7.82 (m, 1H), 7.69-7.66 (m, 2H),7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 5.41-5.39 (m,1H), 5.29-5.27 (m, 1H), 4.34-4.30 (m, 1H), 3.75-3.70 (m, 1H), 3.69 (s,3H), 3.64-3.62 (m, 1H), 3.20-3.01 (m, 1H), 2.99 (s, 2H), 2.95 (s, 2H),2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.78-1.52 (m,8H), 0.88-0.86 (m, 6H).

Step 15) the Preparation of Compound 1-18

To a solution of compound 1-17 (2.1 g, 9.17 mmol) in THF (20.0 mL) wasadded a aqueous solution of NaOH (2.1 g, 20.0 mL). At the end of theaddition, the mixture was stirred at 60° C. overnight. After thereaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (50 mL) and extracted with water (50 mL×3). Thecombined aqueous phase was adjusted to pH 4 with hydrochloric acid (1M)and the solid was precipitated. The resulting mixture was filtered togive the title compound as a yellow solid (1.4 g, 72%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 217 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.59 (d, 1H, J=8.0 Hz), 6.96 (d, 1H,J=1.6 Hz), 6.64 (dd, 1H, J=8.0 Hz, 2.0 Hz).

Step 16) the Preparation of Compound 1-19

To a mixture of compound 1-18 (1.51 g, 7.00 mmol) in dry THF (5.0 mL)was added CDI (0.83 g, 5.12 mmol). At the end of the addition, themixture was stirred at rt for 2.0 hrs. And then NH₃.H₂O (20 mL) wasadded dropwise at 0° C. At the end of the addition, the mixture wasstirred at rt overnight. After the reaction was completed, the solventwas removed. The residue was dissolved in EtOAc (100 mL). The resultingmixture was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound as a pale yellow solid(1.2 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 217 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H, J=8.0 Hz),7.15 (s, 1H), 6.89 (d, 1H, J=2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J=8.0Hz, 2.0 Hz).

Step 17) the Preparation of Compound 1-20

To a suspension of compound 1-19 (1.5 g, 7.00 mmol), compound 1-19-2(2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) andTHF (10.0 mL) was added DIPEA (5.8 mL, 35 mmol) via syringe dropwise at0° C. under N₂. At the end of the addition, the mixture was stirred atrt for 8.0 hrs. After the reaction was completed, the solvent wasremoved. The residue was dissolved in EtOAc (100 mL), and then washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as colorless slurry(0.66 g, 20%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 470.33 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d,1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.57 (d, 1H, J=8.0 Hz), 4.52-4.49(m, 1H), 4.40-4.36 (m, 1H), 3.89-3.86 (m, 2H), 3.68 (s, 3H), 2.24-2.15(m, 2H), 2.09-2.00 (m, 2H), 1.09 (d, 3H, J=6.0 Hz), 0.97 (d, 3H, J=6.0Hz).

Step 18) the Preparation of Compound 1-21

To a solution of compound 1-20 (0.6 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) dropwise at 0°C. At the end of the addition, the mixture was stirred at rt for 5.0hrs. After the reaction was completed, the solvent THF was removed. Theresidue was dissolved in EtOAc (50 mL), and then washed with water andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/3) to give the title compound as a white solid (0.55 g, 96%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 452.33 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.31 (s, 1H), 8.07 (d, 1H, J=8.0 Hz),7.79 (d, 1H, J=2.0 Hz), 7.53 (dd, 1H, J=8.0 Hz, 2.0 Hz), 5.78 (d, 1H,J=8.0 Hz), 5.10 (dd, 1H, J=8.0 Hz, 2.0 Hz), 4.33 (t, 1H, J=8.0 Hz),4.14-4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.66 (s, 3H), 2.53-2.51 (m, 1H),2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.04-1.79 (m, 2H), 0.93 (d, 1H,J=2.0 Hz).

Step 19) the Preparation of Compound 1-22

A suspension of compound 1-21 (0.2 g, 0.44 mmol), compound 1-14-2 (0.13g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.04 g, 0.049 mmol) and KOAc (0.11 g,1.12 mmol) in DMF (5.0 mL) was stirred at 80° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (20 mL) and filtered through a celite pad. The filtrate waswashed with water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=2/1) to give the title compound as ayellow solid (0.16 g, 70%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 499.26 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.08 (s, 1H), 8.22 (d, 1H, J=8.0 Hz),8.11 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 5.71 (d, 1H, J=8.0 Hz), 5.17 (d,1H, J=6.0 Hz), 4.35 (t, 1H, J=8.0 Hz), 4.15-4.10 (m, 1H), 3.88-3.86 (m,1H), 3.67 (s, 3H), 2.71-2.67 (m, 1H), 2.34-2.32 (m, 1H), 2.09-1.99 (m,2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H).

Step 20) the Preparation of Compound 1-23

A mixture of compound 1-22 (0.12 g, 0.23 mmol), compound 1-16 (0.12 g,0.16 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and K₂CO₃ (60 mg, 0.44 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 4.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/25) to give the title compound as a pale yellow solid (74.7 mg,50%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 911.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.21 (s, 1H), 10.46 (s, 1H), 8.28 (s,1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.54-7.51 (m, 2H), 7.46 (s, 2H),7.37-7.33 (m, 2H), 5.70-5.60 (m, 2H), 5.31-5.30 (m, 1H), 5.21-5.20 (m,1H), 4.55-4.35 (m, 2H), 3.95-3.86 (m, 3H), 3.70 (s, 3H), 3.68 (s, 3H),2.98 (s, 4H), 2.69-2.57 (m, 2H), 2.35-2.01 (m, 8H), 2.09-1.99 (m, 2H),0.92-0.84 (m, 12H).

Example 2

Synthetic route:

Step 1) the Preparation of Compound 2-2

MgCl₂ (1.53 g, 16.4 mmol) was added in one portion to a solution ofethyl potassium malonate (3.55 g, 20.85 mmol) in THF (25.0 mL). Thereaction mixture was stirred for 7.0 hrs at 70° C. and then at 30° C.overnight. A solution of compound 2-1 (4.0 g, 16.06 mmol) in THF (10.0mL) was slowly added to a mixture of CDI (3.12 g, 19.25 mmol) in THF(15.0 mL), which was stirred at 30° C. for 2.0 hrs. The solution wasadded to the mixed system of ethyl potassium malonate described above.At the end of the addition, the mixture was stirred overnight at 30° C.After the reaction was completed, the mixture was cooled to 20° C. andneutralized with diluted HCl (4 M). The solution was concentrated invacuo and the product was dissolved in EtOAc (50 mL), washed with 5%aqueous sodium bicarbonate and brine and, then dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=20/1) to give the title compound(4.6 g, 90%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 320.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.19-7.18 (m, 5H), 5.13-5.12 (m, 2H),4.23, 4.21, 4.19, 4.18 (s, s, s, s, 2H), 4.03-3.97 (m, 1H), 3.59, 3.58(s, s, 2H), 3.50-3.43 (m, 1H), 3.32-3.23 (m, 1H), 2.08-1.93 (m, 2H),1.82-1.70 (m, 2H), 1.29-1.25 (t, 3H, J=8.0 Hz).

Step 2) the Preparation of Compound 2-3

To a solution of compound 2-2 (1.0 g, 3.13 mmol) and acetic acid glacial(0.17 mL, 3.13 mmol) in toluene (10.0 mL) was added 4-bromoaniline (0.4g, 2.35 mmol) dropwise at rt. At the end of the addition, the mixturewas refluxed for 6.0 hrs. After the reaction was completed, the solventwas removed. The residue was dissolved in Dowtherm A (5.0 mL) and thenstirred at 235° C. for 1.5 hrs. After the reaction was completed, themixture was cooled to rt, and ether (8.0 mL) followed by heptane (5.0mL) was added. An oily residue precipitated and the solvent wasdecanted. The residue was purified by silica gel column chromatography(DCM/EtOAc (v/v)=1/1) to give the title compound (0.15 g, 11%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 428.9 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd,1H), 7.45, 7.43 (dd, dd, 1H), 7.28-7.22 (m, 5H), 6.58 (t, 1H), 5.14-5.13(m, 2H), 4.98-4.94 (m, 1H), 3.64-3.57 (m, 1H), 3.43-3.36 (m, 1H),2.26-2.17 (m, 1H), 2.09-1.83 (m, 3H).

Step 3) the Preparation of Compound 2-4

To a solution of compound 2-3 (2.13 g, 5.0 mmol) in EtOAc (40.0 mL) wasadded Pd/C (0.2 g). The mixture was stirred at 40° C. under 10 atm of H₂gas for 5.0 hrs. After the reaction was completed, the mixture wasfiltered. The filtrate was concentrated in vacuo to give the titlecompound (1.25 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 293.5 [M+H]⁺.

Step 4) the Preparation of Compound 2-5

To a solution of compound 2-4 (2.92 g, 10.0 mmol), compound 1-13-2 (1.93g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) was addedDIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of the addition,the mixture was stirred at rt for 3.0 hrs. After the reaction wascompleted, the mixture was diluted with DCM (100 mL). The resultingmixture was washed with aqueous NH₄Cl and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=2/1) to give the title compound(2.69 g, 60%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 450.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd,1H), 7.45, 7.43 (dd, dd, 1H), 6.64 (m, 1H), 5.32, 5.29 (dd, dd, 1H),5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.49 (m, 1H),3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 0.97, 0.95 (m,m, 3H), 0.91, 0.89 (m, m, 3H).

Step 5) the Preparation of Compound 2-6

To a mixture of compound 2-5 (0.45 g, 0.91 mmol), compound 1-14-2 (0.46g, 1.82 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (71.0 mg, 0.09 mmol) and KOAc (0.27 g,2.73 mmol) was added DMF (5.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was diluted with EtOAc (60 mL), and then filtered through acelite pad. The filtrate was washed with water (20 mL×3) and brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) togive the title compound (0.38 g, 85%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 498.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.48-8.47 (m, 1H), 8.00, 7.99 (dd, dd,1H), 7.47, 7.45 (dd, dd, 1H), 6.76 (m, 1H), 5.32, 5.29 (dd, dd, 1H),5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.50 (m, 1H),3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 1.23, 1.20 (m,m, 12H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 6) the Preparation of Compound 2-7

A mixture of compound 2-6 (0.30 g, 0.61 mmol), compound 1-16 (0.42 g,0.61 mmol), Pd(PPh₃)₄ (35.3 mg, 0.03 mmol) and K₂CO₃ (0.25 g, 1.83 mmol)in the mixed solvent of DME/H₂O (v/v=5/1, 6.0 mL) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc) to give the title compound (0.31 g, 56%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 455.8 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (m, 1H), 7.72-7.71 (m, 1H),7.70-7.69 (m, 1H), 7.62 (dd, 1H), 7.60-7.56 (m, 4H), 7.52-7.49 (m, 2H),7.00-6.99 (m, 1H), 5.32, 5.29 (dd, dd, 2H), 5.23-5.19 (m, 1H), 5.18-5.13(m, 1H), 4.41-4.36 (m, 1H), 4.27-4.22 (m, 1H), 3.85-3.78 (m, 1H),3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H),2.93-2.88 (m, 4H), 2.30-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89(m, m, 6H).

Example 3

Synthetic route:

Step 1) the Preparation of Compound 3-2

NaH (60%, 3.13 g, 78 mmol) was added to DMSO (100 mL) followed bydropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end ofthe addition, the mixture was stirred at 100° C. for 40 mins. Themixture was cooled to rt, then compound 3-1 (10 g, 35.60 mmol) wasadded, and the mixture was stirred for 30 mins at rt, then heated to100° C. for 1.0 hr. After the reaction was completed, the reaction wasquenched with aqueous saturated NH₄Cl solution (50 mL), and then EtOAc(150 mL) was added to the mixture. The combined organic layer werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuoto give the title compound (11.0 g, 86%), which was used for the nextstep. The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.36-8.35 (m, 1H), 7.73, 7.70 (dd, dd,1H), 7.60, 7.58 (t, t, 1H), 5.24-5.23 (m, 1H), 4.32-4.26 (m, 4H),1.29-1.25 (t, 6H, J=8.0 Hz).

Step 2) the Preparation of Compound 3-3

To a solution of compound 3-2 (11.0 g, 0.64 mmol) in DMSO (100 mL) wasadded LiCl (3.0 g, 70 mmol) and water (0.64 g, 35.6 mmol) slowly at rt.At the end of the addition, the mixture was stirred at 100° C. for 3.0hrs. After the reaction was completed, the mixture was cooled to rt,diluted with 200 mL of EtOAc, washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=50/1) to give the title compoundas a solid (8.0 g, 91%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 287.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.32 (m, 1H), 7.77, 7.75 (m, m, 1H),7.22, 7.20 (m, m, 1H), 4.50 (m, 2H), 4.42-4.36 (m, 2H), 1.42-1.38 (t,3H, J=8.0 Hz).

Step 3) the Preparation of Compound 3-4

NaH (60%, 3.75 g, 93 mmol) was added to a stirred suspension of compound3-3 (8.0 g, 27.8 mmol) in DMF (90.0 mL) at rt. After 15 mins, CH₃I (22.2g, 156 mmol) was added. At the end of the addition, the reaction mixturewas stirred at rt overnight. After the reaction was completed, themixture was poured into a mixture of ice water (200 mL) and EtOAc (200mL). The organic layer was washed with water (200 mL×3) and brine (50mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=200/1)to give the title compound as a solid (7.0 g, 80%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.11-8.10 (m, 1H), 7.58 (m, 2H),4.08-3.94 (m, 2H), 1.62 (s, 6H), 1.08-1.04 (t, 3H, J=8.0 Hz).

Step 4) the Preparation of Compound 3-5

To a solution of compound 3-4 (7.0 g, 22.1 mmol) in MeOH (80.0 mL) andTHF (40.0 mL) was added KOH (2 M, 80 mL, 160 mmol). At the end of theaddition, the mixture was stirred at 80° C. for 5.0 hrs. After thereaction was completed, the mixture was concentrated in vacuo. Theresidue was diluted with water (50 mL), and washed with MTBE (50 mL).The aqueous layer was acidified to pH 2 by addition of HCl (6 M) andthen extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuoto give the title compound (5.0 g, 79%). The compound was characterizedby the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.15 (m, 1H), 7.65, 7.62 (d, d, 1H),7.59, 7.57 (d, d, 1H), 1.64 (s, 6H).

Step 5) the Preparation of Compound 3-6

Compound 3-5 (8.8 g, 30.5 mmol) was dissolved in DCM (200 mL) under N₂.After addition of triethylamine (4.01 g, 39.6 mmol), the mixture wasstirred at rt for 15 mins. Diphenylphosphoryl azide (11 g, 40.0 mmol)was added and the reaction mixture was stirred at rt for 3.0 hrs. Afterremoval of the volatiles in vacuo, the obtained residue was diluted withtoluene (200 mL) and the mixture was refluxed for 2.0 hrs. The mixturewas cooled to rt and HCl (6 M, 100 mL) was added. The resulting solutionwas refluxed for 3.0 hrs. The crude mixture was concentrated in vacuo,diluted with ice water (100 mL) and basified with aq. NaOH (5 M), thenextracted with EtOAc (150 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound (7.1 g, 89%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.90-7.89 (m, 1H), 7.57, 7.54 (d, d,1H), 7.46, 7.44 (d, d, 1H), 1.84 (brs, 2H), 1.58 (s, 6H).

Step 6) the Preparation of Compound 3-7

To a solution of compound 1-10-2 (6.42 g, 29.8 mmol) in DCM (150 mL)were added HATU (20.6 g, 54.2 mmol) and triethylamine (8.22 g, 81.4mmol) dropwise at rt in turn, then the mixture was stirred at rt for 15mins. Compound 3-6 (7.1 g, 27.4 mmol) was added. At the end of theaddition, the mixture was stirred at rt for 1.0 hr. After the reactionwas completed, the mixture was diluted with 150 mL of water. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=20/1) to give the title compound (8.97 g,72%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 456.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.08-8.07 (m, 1H), 7.65 (m, 2H), 6.40(m, 1H), 4.19-4.15 (m, 1H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H),2.28-2.09 (m, 2H), 1.93-1.72 (m, 2H), 1.68 (d, 6H), 1.40 (s, 9H).

Step 7) the Preparation of Compound 3-8

To a solution of compound 3-7 (8.9 g, 19.5 mmol) in MeOH (50.0 mL) wasadded Pt/C (1.0 g). The mixture was stirred at rt under 20 atm of H₂ gasovernight. After the reaction was completed, the mixture was filtered.The filtrate was concentrated in vacuo to give the title compound (8.29g, 100%). The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.07, 7.05 (dd, dd, 1H), 7.04, 7.02(dd, dd, 1H), 6.77 (q, 1H), 6.40 (m, 1H), 4.11-4.07 (m, 1H), 3.98 (brs,2H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.73(m, 2H), 1.69 (d, 6H), 1.40 (s, 9H).

Step 8) the Preparation of Compound 3-9

A solution of compound 3-8 (8.29 g, 19.5 mmol) in acetic acid glacial(100 mL) was stirred at 50° C. for 1.0 hr. After the reaction wascompleted, the mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=7/1) togive the title compound (1.5 g, 19%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 408.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H),7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.14 (brs, 1H), 4.81-4.77 (m,1H), 3.52-3.46 (m, 1H), 3.41-3.34 (m, 1H), 2.52-2.45 (m, 1H), 2.18-2.09(m, 1H), 1.95-1.86 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.64 (m, 3H),1.62-1.61 (m, 3H), 1.42 (s, 9H).

Step 9) the Preparation of Compound 3-10

To a solution of compound 3-9 (1.5 g, 3.68 mmol) in EtOAc (15.0 mL) wasadded a solution of HCl in EtOAc (10.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the mixture was concentrated. The residue waswashed with EtOAc (10 mL) and filtered to give the title compound as apale yellow solid (1.02 g, 90%), which was used for the next stepwithout further purification. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 308.5 [M+H]⁺.

Step 10) the Preparation of Compound 3-11

To a solution of compound 3-10 (3.07 g, 10.0 mmol), compound 1-13-2(1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) wasadded DIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of theaddition, the mixture was stirred at rt for 3.0 hrs. After the reactionwas completed, 50 mL of DCM was added to the mixture. The resultingmixture were washed with aq. NH₄Cl and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=2/1) to give the title compound asa solid (3.94 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 465.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H),7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14(brs, 1H), 4.65-4.61 (m, 1H), 4.32-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54(m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H),1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m,3H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 11) the Preparation of Compound 3-12

To a mixture of compound 3-11 (0.42 g, 0.91 mmol), compound 1-14-2 (0.46g, 1.82 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (71.0 mg, 0.09 mmol) and KOAc (0.27 g,2.73 mmol) was added DMF (5.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was diluted with EtOAc (60 mL). The resulting mixture wasfiltered through a celite pad. The filtrate was washed with water (20mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/1) to give the title compound (0.37 g, 80%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 513.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67, 7.65 (d, d, 1H), 7.48-7.47 (m,1H), 7.26, 7.24 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H),4.65-4.61 (m, 1H), 4.33-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H),3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m,1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.25-1.24(q, 6H), 1.22-1.21 (q, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Step 13) the Preparation of Compound 3-13

To a mixture of compound 3-12 (0.31 g, 0.61 mmol), compound 1-16 (0.42g, 0.61 mmol), Pd(PPh₃)₄ (35.26 mg, 0.03 mmol) and K₂CO₃ (0.25 g, 1.83mmol) were added DME (5.0 mL) and H₂O (1.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 4.0 hrs. After the reaction wascompleted, the mixture was diluted with EtOAc (50.0 mL). The resultingmixture was washed with water (20 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1) to give the title compound(0.34 g, 60%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 463.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H),7.52-7.47 (m, 4H), 7.40-7.38 (dd, dd, 1H), 7.37-7.35 (d, d, 1H), 7.19,7.17 (d, d, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 4.65-4.61 (m,1H), 4.41-4.28 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s,6H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88(m, 2H), 2.40-2.32 (m, 1H), 2.30-1.92 (m, 7H), 1.90-1.82 (m, 1H),1.80-1.71 (m, 1H), 1.69-1.51 (m, 12H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m,m, 6H), 0.90, 0.89 (m, m, 6H).

Example 4

Synthetic route:

Step 1) the Preparation of Compound 4-2

To a solution of compound 4-1 (5.0 g, 69 mmol) in THF (50.0 mL) wasadded compound 4-1-2 (8.34 g, 69 mmol) and Ti(OEt)₄ (20.0 mL). At theend of the addition, the mixture was stirred at 50° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt andquenched with 200 mL of water. The resulting mixture was filtered andthe filtrate was extracted with DCM (50 mL×3). The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM) to give the title compound as a solid (5.55 g,46%). The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.39 (s, 4H), 1.31 (s, 9H).

Step 2) the Preparation of Compound 4-3

To a solution of compound 4-2-2 (3.0 g, 9.18 mmol) in THF (20.0 mL) wasadded n-BuLi (4.4 mL, 2.5 M) dropwise via syringe at −78° C. under N₂.At the end of the addition, the mixture was stirred at −78° C. for 15mins. Compound 4-2 (1.92 g, 11 mmol) was added to the mixture. Thereaction was stirred at −78° C. for 30 mins and then stirred at r.t foranother 5.0 hrs. After the reaction was completed, the mixture waspoured into ice water (50 mL). The resulting mixture layer was extractedwith DCM (20 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) togive the title compound (1.3 g, 38%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 378.7 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.14-8.13 (m, 1H), 7.69, 7.67 (d, d,1H), 7.43, 7.41 (d, d, 1H), 4.45 (brs, 1H), 4.36, 4.35 (brs, brs, 2H),4.15, 4.13 (brs, brs, 2H), 1.21 (s, 9H).

Step 3) the Preparation of Compound 4-4

To a solution of compound 4-3 (1.3 g, 3.45 mmol) in MeOH (10.0 mL) wasadded a solution of HCl in 1,4-dioxane (10.0 mL, 4 M) dropwise. At theend of the addition, the mixture was stirred at rt for 30 mins, and thenthe mixture was concentrated in vacuo. The residue was dissolved in DCM(10 mL), then compound 1-10-2 (0.84 g, 3.94 mmol), HATU (1.49 g, 3.94mmol) and triethylamine (0.66 g, 6.56 mmol) were added to the mixture inturn. At the end of the addition, the reaction was stirred at rt for 1.0hr. After the reaction was completed, the mixture was quenched withwater (20 mL) and the organic phase was separated. The aqueous layer wasextracted with DCM (20 mL×2). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the compound (a) (1.27 g). To a solution of compound(a) (1.0 g, 2.1 mmol) in mixed solvent of MeOH and water (20 mL,v/v=1/1) were added Fe (0.35 g, 6.3 mmol) and NH₄Cl (0.55 g, 10.5 mmol)in turn. At the end of the addition, the mixture was refluxed for 3.0hrs. After the reaction was cooled to rt, the mixture was concentratedin vacuo, and then 10 mL of water was added. The resulting mixture wasextracted with DCM (10 mL×2). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in glacial acetic acid (20 mL) and stirred at 80°C. for 30 mins. After the reaction was completed, the mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/1) to give the title compound (0.96 g,66%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 422 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.40, 7.37 (d, d, 1H), 7.19 (q, 1H),6.91, 6.88 (d, d, 1H), 5.14 (brs, 1H), 4.82-4.78 (m, 1H), 4.45-4.39 (m,2H), 4.23-4.18 (m, 2H), 3.62-3.55 (m, 1H), 3.44-3.36 (m, 1H), 2.24-2.16(m, 1H), 2.11-2.01 (m, 1H), 2.00-1.91 (m, 1H), 1.89-1.79 (m, 1H), 1.43(s, 9H).

Step 4) the Preparation of Compound 4-5

To a solution of compound 4-4 (0.49 g, 1.16 mmol) in EtOAc (5.0 mL) wasadded a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the mixture was concentrated. The residue waswashed with EtOAc (10.0 mL) and filtered to give the title compound as apale yellow solid (0.36 g, 95%), which was used for the next stepwithout further purification. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 322.5 [M+H]⁺.

Step 5) the Preparation of Compound 4-6

To a solution of compound 4-5 (1.6 g, 5.0 mmol), compound 1-13-2 (0.97g, 5.5 mmol) and EDCI (1.05 g, 5.5 mmol) in DCM (15.0 mL) was addedDIPEA (3.3 mL, 19.95 mmol) dropwise at 0° C., and the mixture wasstirred at rt for 3.0 hrs. After the reaction was completed, the mixturewas diluted with DCM (50 mL). The resulting mixture was washed with aqNH₄Cl and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound (1.91 g, 80%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 479.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.40, 7.37 (d, d, 1H), 7.19 (q, 1H),6.91, 6.88 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H), 4.89-4.85(m, 1H), 4.45-4.39 (m, 2H), 4.33-4.28 (m, 1H), 4.23-4.18 (m, 2H), 3.63(s, 3H), 3.62-3.56 (m, 1H), 3.26-3.18 (m, 1H), 2.34-2.27 (m, 1H),2.10-2.01 (m, 1H), 1.99-1.83 (m, 2H), 1.81-1.71 (m, 1H), 0.97, 0.95 (m,m, 3H), 0.90, 0.89 (m, m, 3H).

Step 6) the Preparation of Compound 4-7

To a mixture of compound 4-6 (2.39 g, 5.0 mmol), compound 1-14-2 (1.52g, 6.0 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.41 g, 0.5 mmol) and KOAc (1.23 g,12.5 mmol) was added DMF (10.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was diluted with EtOAc (150 mL). The resulting mixture wasfiltered through a celite pad. The filtrate was washed with water (60mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/2) to give the title compound (2.1 g, 80%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 527.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.73, 7.71 (d, d, 1H), 7.36, 7.34 (d,d, 1H), 7.21 (m, 1H), 5.32, 5.30 (d, d, 1H), 5.14 (brs, 1H), 4.89-4.85(m, 1H), 4.44-4.39 (m, 2H), 4.33-4.28 (m, 1H), 4.23-4.18 (m, 2H), 3.63(s, 3H), 3.62-3.56 (m, 1H), 3.26-3.18 (m, 1H), 2.34-2.27 (m, 1H),2.10-2.01 (m, 1H), 1.99-1.83 (m, 2H), 1.81-1.71 (m, 1H), 1.25-1.24 (m,6H), 1.22-1.21 (m, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H)3H).

Step 7) the Preparation of Compound 4-8

To a mixture of compound 4-7 (0.32 g, 0.61 mmol), compound 1-16 (0.42 g,0.61 mmol), Pd(PPh₃)₄ (35.3 mg, 0.03 mmol) and K₂CO₃ (025 g, 1.83 mmol)were added DME (5.0 mL) and H₂O (1.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 4.0 hrs. After the reaction wascompleted, the mixture was diluted with EtOAc (50 mL). The resultingmixture was washed with water (20 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc) to give the title compound as a beigesolid (0.34 g, 60%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 470.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H),7.52-7.48 (m, 3H), 7.41-7.38 (m, 2H), 7.37, 7.35 (dd, dd, 1H), 7.29,7.27 (dd, dd, 1H), 5.32, 5.30 (d, d, 2H), 5.23-5.19 (m, 1H), 4.89-4.85(m, 1H), 4.41-4.36 (m, 1H), 4.31-4.28 (m, 3H), 4.15-4.09 (m, 2H),3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.62-3.56 (m, 1H),3.26-3.18 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88 (m, 2H), 2.34-1.33 (m,18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 5

Synthetic route:

Step 1) the Preparation of Compound 5-2

To a solution of compound 5-1 (5.0 g, 22.7 mmol) in EtOH (60.0 mL) wasadded a suspension of Na₂SO₃ (7.16 g, 56.8 mmol) in EtOH (100 mL) andwater (125 mL) dropwise. At the end of the addition, the suspension wasstirred at 70° C. for 15 hrs. After the reaction was completed, themixture was cooled to rt, and the reaction was acidified with HCl (2 M)to pH 2, and then concentrated in vacuo. The residue was dissolved underreflux in brine (100 mL). Subsequently, water (10.0 mL) was added andthe solution was cooled in an ice bath. The precipitate was collected byfiltration, resulting in compound 5-2 (5.70 g, 89%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 282.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.75 (br, 1H), 8.31 (m, 1H), 8.07 (m,2H).

Step 2) the Preparation of Compound 5-3

To a solution of compound 5-2 (3.0 g, 10.6 mmol) in toluene (50.0 mL)and DMF (1 drop) was added thionyl chloride (5.0 mL). At the end of theaddition, the reaction was refluxed for 4.0 hrs. After the reaction wascompleted, the mixture was cooled and concentrated in vacuo. The residuewas dissolved in toluene (4.0 mL), and then to the resulting mixture wasadded a mixture of concentrated aqueous ammonium hydroxide solution (1.0mL) and THF (10.0 mL) at −10° C. After stirring for 2.0 hrs, thereaction was acidified with hydrochloric acid (6 M) to pH 4. The organiclayer was separated and then dried over anhydrous Na₂SO₄ andconcentrated in vacuo. PE (15.0 mL) was added to the resulting slurryand the product was collected by vacuum filtration to afford compound5-3 (2.12 g, 71.4%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 281.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.18, 8.17 (d, d, 1H), 8.03, 8.00 (d,d, 1H), 7.84, 7.81 (d, d, 1H), 5.47 (br, 2H).

Step 3) the Preparation of Compound 5-4

A suspension of compound 5-3 (2.12 g, 7.5 mmol) in HI (25.0 mL, 57% aq.)was stirred at 90° C. for 4.0 hrs. After cooling to rt, the dark purplemixture was diluted with EtOAc (50 mL) and washed successively withsaturated aq. Na₂S₂O₃, saturated aq NaHCO₃ and brine. The colorlessorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo. The crude product was purified by high-performance liquidchromatography (eluent: CH₃CN/H₂O from 22/78 to 52/48 with 0.01% NH₃.H₂Oas buffer), resulting in compound 5-4 (1.86 g, 98%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 251.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.62-7.60 (m, 1H), 7.18-7.15 (m, 2H),4.85 (brs, 4H).

Step 4) the Preparation of Compound 5-5

To a solution of compound 5-4 (1.86 g, 7.4 mmol) in acetone (20.0 mL)was added triethylamine (4.05 mL, 29.6 mmol) dropwise. Compound 5-4-2(1.28 g, 4.8 mmol) was added to the reaction at 0° C. After stirring for5.0 hrs, the mixture was diluted with water (10 mL) and acidified withhydrochloric acid (2 M) to pH 4. The resulting precipitate was collectedby filtration and then transferred to another flask. A solution of K₂CO₃(1.5 g, 10.87 mmol) in water (10 mL) was added and then the mixture wasrefluxed for 2.0 hrs. The reaction was acidified with hydrochloric acid(2 M) to pH 4. The precipitate was filtered off and washed with water.The crude product was purified by high-performance liquid chromatography(eluent: CH₃CN/H₂O from 35/65 to 65/35 with 0.75% CF₃COOH as buffer),resulting in compound 5-5 (1.00 g, 45%). The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 464.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m,1H), 7.43, 7.41 (d, d, 1H), 7.28-7.22 (m, 5H), 6.30 (brs, 1H), 5.14-5.13(m, 2H), 4.86-4.80 (m, 1H), 3.68-3.62 (m, 1H), 3.50-3.43 (m, 1H),2.22-1.98 (m, 4H).

Step 5) the Preparation of Compound 5-6

To a solution of compound 5-5 (3.73 g, 8.03 mmol) in EtOAc (40.0 mL) wasadded a catalytic amount of Pd/C (0.35 g), then the mixture was stirredat 40° C. under 10 atm of H₂ gas for 5.0 hrs. After the reaction wascompleted, the mixture was filtered, the filtrate was concentrated invacuo to give the title compound 5-6 (2.27 g, 86%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 330.5 [M+H]⁺.

Step 6) the Preparation of Compound 5-7

To a suspension of compound 5-6 (3.29 g, 10.0 mmol), compound 1-13-2(1.93 g, 11.0 mmol) and EDCI (2.10 g, 11.0 mmol) in DCM (30.0 mL) wasadded DIPEA (6.6 mL, 39.9 mmol) dropwise at 0° C. At the end of theaddition, the mixture was stirred at rt for 3.0 hrs. After the reactionwas completed, the mixture was diluted with DCM (50 mL). The resultingmixture was washed successively with water (30 mL×3), saturated aq.NH₄Cl and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound (2.43 g, 50%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 487.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.93, 7.90 (d, d, 1H), 7.77-7.76 (m,1H), 7.43, 7.41 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H),5.08-5.04 (m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H),3.26-3.18 (m, 1H), 2.38-2.31 (m, 1H), 2.10-1.97 (m, 2H), 1.91-1.71 (m,2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 7) the Preparation of Compound 5-8

A mixture of compound 5-7 (0.44 g, 0.91 mmol), compound 1-14-2 (0.46 g,1.82 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (71.0 mg, 0.09 mmol) and KOAc (0.27 g,2.73 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After cooling to rt, the mixture was diluted with EtOAc (50.0 mL) andfiltered through a celite pad. The filtration was washed with water (20mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound (0.43 g, 88%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 535.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02 (t, 1H), 7.80, 7.78 (d, d, 1H),7.46, 7.44 (d, d, 1H), 6.30 (brs, 1H), 5.32, 5.29 (d, d, 1H), 5.08-5.04(m, 1H), 4.31-4.26 (m, 1H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 3.26-3.18(m, 1H), 2.38-2.31 (m, 1H), 2.10-1.97 (m, 2H), 1.91-1.71 (m, 2H), 1.32,1.29 (m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 8) the Preparation of Compound 5-9

To a mixture of compound 5-8 (0.33 g, 0.61 mmol), compound 1-16 (0.42 g,0.61 mmol), Pd(PPh₃)₄ (35.26 mg, 0.03 mmol) and K₂CO₃ (0.25 g, 1.83mmol) were added DME (5.0 mL) and H₂O (1.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 4.0 hrs. After the reaction wascompleted, the mixture was diluted with EtOAc (50 mL). The resultingmixture was washed with water (20 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc) to give the title compound (0.38 g, 65%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 474.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.27 (brs, 2H), 7.89 (q, 1H), 7.75,7.73 (d, d, 1H), 7.60-7.57 (m, 4H), 7.52-7.48 (m, 3H), 7.47, 7.45 (dd,dd, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 5.08-5.04 (m, 1H),4.41-4.37 (m, 1H), 4.31-4.26 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m,1H), 3.63 (s, 6H), 3.60-3.57 (m, 1H), 3.26-3.18 (m, 1H), 2.97-2.94 (m,2H), 2.92-2.89 (m, 2H), 2.38-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.91,0.89 (m, m, 6H).

Example 6

Synthetic Route:

Step 1) the Preparation of Compound 6-1

To a mixture of compound 1-22 (0.64 g, 1.28 mmol), compound 1-8 (0.27 g,0.61 mmol), Pd(PPh₃)₄ (35.26 mg, 0.03 mmol) and K₂CO₃ (0.25 g, 1.83mmol) were added DME (5.0 mL) and H₂O (1.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 4.0 hrs. After the reaction wascompleted, the mixture was diluted with EtOAc (50 mL). The resultingmixture was washed with water (20 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (EtOAc) to give the title compound (0.33 g, 60%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 457.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.90 (m, 3H), 7.83, 7.81 (d, d,1H), 7.59, 7.57 (d, d, 1H), 7.55-7.50 (m, 2H), 6.72-6.71 (m, 1H),6.08-6.05 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.21-5.15 (m, 1H),5.10-5.05 (m, 1H), 4.30-4.25 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H),3.60-3.54 (m, 1H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.24-3.16 (m,1H), 3.02-2.99 (m, 2H), 2.91-2.87 (m, 2H), 2.50-2.27 (m, 3H), 2.15-2.02(m, 5H), 1.93-1.73 (m, 2H), 1.69-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02,1.00 (m, m, 6H), 0.93, 0.91 (m, m, 6H).

Example 7

Synthetic Route:

Step 1) the Preparation of Compound 7-1

To a mixture of compound 1-22 (0.30 g, 0.61 mmol), compound 1-8 (0.27 g,0.61 mmol), Pd(PPh₃)₄ (35.3 mg, 0.03 mmol) and K₂CO₃ (0.25 g, 1.83 mmol)were added DME (5.0 mL) and H₂O (1.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 4.0 hrs. After the reaction wascompleted, the mixture was diluted with EtOAc (50 mL). The resultingmixture was washed with water (20 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound(0.34 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 691.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.90-7.89 (m, 1H), 7.71, 7.69 (d, d,1H), 7.64, 7.62 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.29, 7.27 (d, d,1H), 5.32, 5.29 (d, d, 1H), 5.21-5.15 (m, 1H), 4.30-4.25 (m, 1H), 3.63(s, 3H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 2.91-2.87 (m, 2H),2.85-2.81 (m, 2H), 2.50-2.42 (m, 1H), 2.37-2.27 (m, 1H), 2.11-1.98 (m,2H), 1.93-1.83 (m, 1H), 1.74-1.42 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.91,0.89 (m, m, 3H).

Step 2) the Preparation of Compound 7-2

To a solution of compound 1-10-2 (10.0 g, 46.6 mmol) in THF (100 mL) wasadded diborane (100 mL, 1M in THF) via syringe at 0° C. under N₂. At theend of the addition, the mixture was stirred at 0° C. for 3.0 hrs. Afterthe reaction was completed, the mixture was quenched with MeOH (80 mL),and the resulting mixture was concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=3/2) togive the title compound 7-2 as colorless oil (7.04 g, 75.2%). Thecompound was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 3.99-3.87 (br, 1H), 3.68-3.51 (m, 2H),3.48-3.39 (m, 1H), 3.34-3.25 (m, 1H), 2.05-1.92 (m, 2H), 1.88-1.71 (m,2H), 1.45 (s, 9H).

Step 3) the Preparation of Compound 7-3

To a solution of compound 7-2 (7.0 g, 34.8 mmol) in DCM (250 mL) wasadded Dess-Martin periodinane (20.7 g, 48.8 mmol) portionwise at 0° C.At the end of the addition, the mixture was stirred at rt for 2.0 hrs.After the reaction was completed, 250 mL of water was added to themixture, and the resulting mixture was filtered. After the layers werepartitioned, the organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=3/2) to give the titlecompound 7-3 as colorless oil (3.5 g, 50.7%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.46 (d, 1H, J=2.8 Hz), 4.08-4.03 (m,1H), 3.51-3.42 (m, 2H), 1.91-1.84 (m, 2H), 2.01-1.93 (m, 2H), 1.43 (s,9H).

Step 4) the Preparation of Compound 7-4

To a solution of compound 7-3 (3.5 g, 17.6 mmol) and ammonia (13 mL) inMeOH (30.0 mL) was added glyoxal (8 mL, 40% in H₂O) dropwise at 0° C. Atthe end of the addition, the mixture was stirred at rt overnight. Afterthe reaction was completed, the mixture was concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=3/2) to give the title compound 7-4 as a white solid (2.0 g,47.6%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 238.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.96 (s, 1H), 4.94 (dd, 1H, J=7.68,2.40 Hz), 3.38 (t, 2H, J=6.24 Hz), 2.17-2.03 (m, 2H), 1.99-1.91 (m, 2H),1.48 (s, 9H).

Step 5) the Preparation of Compound 7-5

To a solution of compound 7-4 (2.0 g, 8.4 mmol) in DCM (60.0 mL) wasadded N-iodosuccinimide (3.8 g, 16.8 mmol) at 0° C. portionwise, and themixture was stirred at 0° C. for 1.5 hrs. After the reaction wascompleted, the mixture was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=3/2) to give the title compound7-5 as a white solid (2.6 g, 63.1%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 490.0 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.89 (dd, 1H, J=7.64, 2.52 Hz), 3.36(t, 2H), 2.14-2.02 (m, 2H), 1.97-1.85 (m, 2H), 1.49 (s, 9H).

Step 6) the Preparation of Compound 7-6

To a suspension of compound 7-5 (1.6 g, 3.27 mmol) in mixed solvent ofethanol and water (50.0 mL, v/v=3/7) was added Na₂SO₃ (3.7 g, 29 mmol),and the mixture was refluxed for 17 hrs. After the reaction wascompleted, ethanol was removed in vacuo, and 20 mL of water was added tothe mixture. The resulting mixture was extracted with EtOAc (30 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=3/2) to give the title compound 7-6 as awhite solid (1.0 g, 84%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 364.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.04 (d, 1H, J=1.84 Hz), 4.89 (dd, 1H,J=7.72 Hz, 2.56 Hz), 3.36 (t, 2H), 2.18-2.03 (m, 2H), 1.97-1.82 (m, 2H),1.47 (s, 9H).

Step 7) the Preparation of Compound 7-7

To a solution of compound 7-6 (1.50 g, 4.1 mmol) in EtOAc (10.0 mL) wasadded a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt overnight. After thereaction was completed, the mixture was filtered, and the filter cake(1.2 g) was used for the next step without further purification. Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 264.1 [M+H]⁺.

Step 8) the Preparation of Compound 7-8

A suspension of compound 7-7 (1.2 g, 3.6 mmol), compound 1-13-2 (0.69 g,3.9 mmol) and EDCI (0.75 g, 3.9 mmol) in DCM (20.0 mL) was stirred at 0°C. for 5 mins, then DIPEA (2.38 mL, 14.4 mmol) was added dropwise. Atthe end of the addition, the mixture was stirred at rt for 2.0 hrs.After the reaction was completed, the mixture was diluted with DCM (40mL). The resulting mixture was washed with saturated NH₄Cl aqueoussolution, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/EtOH(v/v)=50/1) to give the title compound as a pale yellow solid (1.31 g,86.8%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 421.1[M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.35 (s, 1H), 5.32, 5.29 (brs, brs,1H), 5.20-5.15 (m, 1H), 4.41-4.37 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65(m, 1H), 3.63 (s, 3H), 2.28-2.17 (m, 3H), 2.11-1.96 (m, 2H), 0.97-0.95(m, 3H), 0.91-0.89 (m, 3H).

Step 9) the Preparation of Compound 7-9

To a mixture of compound 7-8 (0.58 g, 1.38 mmol), CuI (78 mg, 0.41mmol), tetrabutylammonium iodide (1.53 g, 4.14 mmol) and PdCl₂(PPh₃)₂(98 mg, 0.14 mmol) in DMF (5.0 mL) was added Et₃N (2.0 mL) via syringeunder N₂. The mixture was stirred at rt for 10 mins, thentrimethylsilylacetylene (0.98 mL, 6.89 mmol) was added. The resultingmixture was stirred at 70° C. overnight. After the reaction wascompleted, the mixture was filtered through a celite pad. The filtratewas diluted with water (20 mL). The aqueous layer was extracted withEtOAc (20 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=3/1) to give the title compound(0.3 g, 55.8%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 391.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.27 (s, 1H), 5.32, 5.30 (d, d, 1H),5.29-5.24 (m, 1H), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.65 (m,1H), 3.63 (s, 3H), 2.31-1.93 (m, 5H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89(m, m, 3H), 0.32 (m, 9H).

Step 10) the Preparation of Compound 7-10

A solution of compound 7-9 (0.34 g, 0.87 mmol) and K₂CO₃ (0.60 g, 4.35mmol) in mixed solvent of MeOH (2.0 mL) and THF (2.0 mL) was stirred atrt for 6.0 hrs. After the reaction was completed, the mixture wasconcentrated. The residue was diluted with water (10 mL) and thenextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound (0.23 g, 82.6%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 319.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.27 (s, 1H), 5.35-5.31 (m, 1.5H),5.30-5.29 (d, 0.5H, J=4.0 Hz), 4.41-4.36 (m, 1H), 3.89-3.83 (m, 1H),3.73-3.66 (m, 1H), 3.63 (s, 3H), 3.36 (s, 1H), 2.31-1.93 (m, 5H), 0.97,0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 11) the Preparation of Compound 7-11

To a mixture of compound 7-1 (0.27 g, 0.39 mmol), compound 7-10 (0.14 g,0.43 mmol), CuI (33 mg, 0.172 mmol), PdCl₂(PPh₃)₂ (14.1 mg, 0.02 mmol)and PPh₃ (0.23 g, 0.86 mmol) were added anhydrous DMF (10.0 mL) and Et₃N(5.0 mL) in turn via syringe under N₂. At the end of the addition, themixture was stirred at rt for 10 mins and stirred at 90° C. for another5.0 hrs. After the reaction was completed, the mixture was filtratedthrough a celited pad. The filtrated was diluted with water (20 mL) andthen extracted with EtOAc (20 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=60/1) to give the title compound (0.2 g, 58.7%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 859.5 [M+H]⁺; and

¹H NMR (400 MHz, CD₃OD) δ (ppm): 8.02-8.01 (m, 1H), 7.64, 7.62 (d, d,1H), 7.52, 7.50 (d, d, 1H), 7.48 (s, 1H), 7.47, 7.45 (dd, dd, 1H), 7.30,7.28 (dd, dd, 1H), 5.51-5.47 (m, 1H), 5.32, 5.30 (d, d, 2H), 5.21-5.15(m, 1H), 4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.89-3.83 (m, 1H),3.73-3.66 (m, 1H), 3.63 (s, 6H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H),3.15-3.11 (m, 2H), 2.81-2.78 (m, 2H), 2.50-2.42 (m, 1H), 2.31-1.83 (m,9H), 1.73-1.52 (m, 6H), 1.48-1.37 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90,0.89 (m, m, 6H).

Example 8

Synthetic Route:

Step 1) the Preparation of Compound 8-1

To a solution of formic acid (3.7 mL) was added triethylamine (5.4 mL)at 0° C., followed by 2,5-dimethoxybenzaldehyde (2.0 g, 12 mmol) and2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12 mmol). At the end of theaddition, the mixture was stirred at 100° C. for 2.0 hrs. After thereaction was completed, 20 mL of ice water was added to the mixture, andthe resulting mixture was adjusted to pH 1 with hydrochloric acid (2 M)and extracted with EtOAc (25 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) togive the title compound 8-1 as a white solid (0.21 g, 83%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 211.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.78-6.70 (m, 6H), 3.78 (s, 3H), 3.75(s, 3H), 2.91 (t, 2H, J=7.8 Hz), 2.65 (t, 2H, J=7.8 Hz).

Step 2) the Preparation of Compound 8-2

A mixture of compound 8-1 (4.68 g, 22.3 mmol) and PPA (50.87 g, 24.8 mL)was stirred at 80° C. for 4.0 hrs. After the reaction was completed, 250mL of ice water was added to the mixture, and the resulting mixture wasextracted with EtOAc (100 mL×5). The combined organic layers were washedwith NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=3/1) to give the title compound 8-2 as apale yellow solid (3.0 g, 70.0%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 193.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.98 (d, 1H, J=8.7 Hz), 6.73 (d, 1H,J=8.7 Hz), 3.90 (s, 3H), 3.85 (s, 3H), 3.00-2.97 (m, 2H), 2.68-2.65 (m,2H).

Step 3) the Preparation of Compound 8-3

To a suspension of potassium tert-butanolate (1.17 g, 10.41 mmol) intoluene (10.0 mL) was added a solution of compound 8-2 (0.80 g, 4.16mmol) and 1,5-dibromopentane (0.62 mL, 4.58 mmol) in toluene (20.0 mL)via syringe at 0° C. under N₂. At the end of the addition, the mixturewas stirred at 110° C. for 2.5 hrs. After the reaction was completed,the mixture was quenched with ice-water (50 mL). The aqueous phase wasextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a pale yellow solid (0.63 g,58%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 261.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.98 (d, 1H, J=8.7 Hz), 6.73 (d, 1H,J=8.7 Hz), 3.89 (s, 3H), 3.86 (s, 3H), 2.88 (s, 2H), 1.82-1.68 (m, 5H),1.51-1.26 (m, 5H).

Step 4) the Preparation of Compound 8-4

To a suspension of compound 8-3 (0.99 g, 3.8 mmol) and triethylsilane(3.7 mL, 23 mmol) was added TFA (8.0 mL) via syringe at 0° C. under N₂.At the end of the addition, the mixture was stirred at 40° C. for 7.0hrs. After the reaction was completed, the mixture was concentrated invacuo. The residue was dissolved in EtOAc (50 mL). The resulting mixturewas washed with saturated Na₂CO₃ aqueous solution and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the titlecompound (0.81 g, 87%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 247.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.61 (s, 2H), 3.79 (s, 6H), 2.74 (s,4H), 1.58-1.40 (m, 10H).

Step 5) the Preparation of Compound 8-5

To a solution of compound 8-4 (0.78 g, 3.17 mmol) in DCM (20.0 mL) wasadded boron tribromide (1.20 mL, 12.67 mmol) dropwise at −78° C. At theend of the addition, the mixture was stirred at −78° C. for 10 mins, andthen stirred at rt for another 1.0 hr. After the reaction was completed,the mixture was quenched with ice water (50 mL). The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound (0.7 g, 100%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 219.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.49 (s, 2H), 5.07-4.53 (br, 2H), 2.68(s, 4H), 1.59-1.37 (m, 10H).

Step 6) the Preparation of Compound 8-6

To a solution of compound 8-5 (0.69 g, 3.16 mmol) in DCM (20.0 mL) wasadded pyridine (2.03 mL, 25.29 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (3.19 mL,19.97 mmol) was added, and then the mixture was stirred at rt for 1.0hr. After the reaction was completed, the mixture was quenched with icewater (20 mL). The aqueous layer was extracted with DCM (30 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/DCM (v/v)=6/1) to give the title compound ascolorless oil (1.11 g, 73%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.13 (s, 2H), 2.92 (s, 4H), 1.59-1.41(m, 10H).

Step 7) the Preparation of Compound 8-7

To a mixture of compound 8-6 (3.84 g, 7.98 mmol), compound 1-15 (3.3 g,6.65 mmol), Pd(PPh₃)₄ (0.77 g, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9 mmol)were added DME (50.0 mL) and H₂O (10.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 3.0 hrs. After the reaction wascompleted, the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (150 mL). The resulting mixture was washed with water(50 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=100/1) to give the title compound (3.5 g, 75%). Thecompound was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H),7.25, 7.23 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H),4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m, 1H), 3.63 (s, 3H),2.82-2.78 (m, 2H), 2.72-2.69 (m, 2H), 2.30-1.92 (m, 5H), 1.77-1.65 (m,4H), 1.57-1.49 (m, 4H), 1.29-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90,0.89 (m, m, 3H).

Step 8) the Preparation of Compound 8-9

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 8-8 (2.99g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) via syringe at 0° C. underN₂. At the end of the addition, the mixture was stirred at rt for 8.0hrs. After the reaction was completed, the solvent was removed. Theresidue was dissolved in EtOAc (100 mL), and then washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) togive the title compound as colorless slurry (0.84 g, 25%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 483.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.54, 7.52 (dd, dd,1H), 7.51, 7.48 (m, m, 1H), 6.39 (s, 2H), 5.57-5.56, 5.55-5.54 (d, d,1H, J=4.0 Hz), 4.50-4.45 (m, 1H), 4.32-4.28 (m, 1H), 3.64 (s, 3H),3.57-3.50 (m, 1H), 3.44-3.36 (m, 1H), 2.17-2.03 (m, 2H), 1.96-1.86 (m,1H), 1.84-1.65 (m, 2H), 1.42-1.31 (m, 1H), 1.12-0.99 (m, 1H), 0.90-0.83(m, 6H).

Step 9) the Preparation of Compound 8-10

To a solution of compound 8-9 (0.62 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.

After the reaction was completed, the solvent THF was removed. Theresidue was dissolved in EtOAc (50 mL), and then washed with water andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) togive the title compound as a white solid (0.56 g, 95%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 465.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.74 (m, 2H), 7.72, 7.70 (d, d,1H), 5.39, 5.36 (d, d, 1H), 5.02-4.97 (m, 1H), 4.34-4.30 (m, 1H), 3.63(s, 3H), 3.51-3.43 (m, 1H), 3.41-3.34 (m, 1H), 2.24-2.15 (m, 1H),2.12-1.98 (m, 3H), 1.94-1.84 (m, 1H), 1.61-1.51 (m, 1H), 1.25-1.12 (m,1H), 1.00-0.98 (m, 3H), 0.92-0.88 (m, 3H).

Step 10) the Preparation of Compound 8-11

A suspension of compound 8-10 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.049 mmol) and KOAc (0.11 g,1.12 mmol) in DMF (5.0 mL) was stirred at 80° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (20 mL) and filtered through a celite pad. The filtrate waswashed with water (10 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=2/1) to give the title compound as ayellow solid (182 mg, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 513.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.80 (m, 1H),7.47, 7.45 (d, d, 1H), 5.39, 5.36 (d, d, 1H), 5.03-4.97 (m, 1H),4.34-4.30 (m, 1H), 3.63 (s, 3H), 3.51-3.43 (m, 1H), 3.41-3.34 (m, 1H),2.24-2.15 (m, 1H), 2.12-1.98 (m, 3H), 1.96-1.83 (m, 1H), 1.61-1.51 (m,1H), 1.32 (q, 6H), 1.29 (q, 6H), 1.25-1.12 (m, 1H), 1.00-0.98 (m, 3H),0.92-0.88 (m, 3H).

Step 11) the Preparation of Compound 8-12

A mixture of compound 8-11 (0.12 g, 0.23 mmol), compound 8-7 (0.12 g,0.16 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and K₂CO₃ (60 mg, 0.44 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 4.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/25) to give the title compoundas a pale yellow solid (76.9 mg, 50%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 469.5 [M+H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (m, 1H), 7.72-7.71, 7.70-7.69 (d,d, 1H, J=4.0 Hz), 7.62-7.57 (m, 5H), 7.52-7.49 (m, 2H), 7.43, 7.41 (dd,dd, 1H), 7.00-6.99 (m, 1H), 5.99-5.98, 5.97-5.96 (d, d, 1H, J=4.0 Hz),5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 5.15-5.09 (m, 1H), 4.41-4.36(m, 1H), 4.32-4.27 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.66 (m, 1H), 3.65(s, 3H), 3.63 (s, 3H), 3.55-3.49 (m, 1H), 3.17-3.09 (m, 1H), 2.85-2.81(m, 4H), 2.30-1.76 (m, 10H), 1.73-1.60 (m, 4H), 1.56-1.48 (m, 4H),1.46-1.37 (m, 1H), 1.29-1.21 (m, 2H), 1.17-1.05 (m, 1H), 0.97, 0.95 (m,m, 3H), 0.90, 0.89 (m, m, 3H), 0.87, 0.85 (m, m, 3H), 0.84-0.83 (m, 3H).

Example 9

Synthetic Route:

Step 1) the Preparation of Compound 9-2

To a solution of compound 9-1 (11.0 g, 44.84 mmol) in DCM (200 mL) wasadded Et₂NSF₃ (8.85 mL, 67.3 mmol) dropwise at −78° C. At the end of theaddition, the mixture was stirred at −78° C. for 2.0 hrs and then at rtfor another 19 hrs. After the reaction was completed, the reaction wasquenched with NH₄Cl aqueous solution (100 mL). The aqueous layer wasextracted with DCM (100 mL×3), and the combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=20/1) togive the title compound as a pale yellow liquid (7.76 g, 70%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 248.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.26, 5.13 (d, d, 1H), 4.55-4.41 (m,1H), 3.88-3.74 (m, 1H), 3.73 (s, 3H), 3.64-3.58 (m, 1H), 2.52-2.44 (m,1H), 2.40-2.32 (m, 1H), 1.42-1.47 (d, 9H, J=20 Hz).

Step 2) the Preparation of Compound 9-3

To a solution of compound 9-2 (5.83 g, 23.58 mmol) in THF (30.0 mL) wasadded LiOH aqueous solution (1.98 g, 30.0 mL) at 0° C., and the mixturewas stirred at rt for 2.0 hrs and then adjusted to pH 5 with dilutedhydrochloric acid (1 M). The solvent THF was removed in vacuo. Theaqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M)and extracted with EtOAc (80 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo to give the title compoundas a white solid (5.3 g, 96%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 234.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.76 (brs, 1H), 5.28-5.12 (m, 1H),4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d,9H, J=16 Hz).

Step 3) the Preparation of Compound 9-4

To a solution of compound 9-3 (5.0 g, 21.45 mmol) and compound 1-10(4.93 g, 17.87 mmol) in DCM (100 mL) was added TEA (4.34 g, 42.9 mmol)dropwise at 0° C. At the end of the addition, the mixture was stirred atrt for 3.0 hrs. After the reaction was completed, the reaction wasquenched with water (50 mL), and the resulting mixture was extractedwith DCM (60 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the titlecompound (3.74 g, 52.2%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 403.3 [M+H]⁺.

Step 4) the Preparation of Compound 9-5

A mixture of compound 9-4 (4.5 g, 11.19 mmol) and ammonium acetate (12.5g, 162 mmol) in toluene (50.0 mL) was refluxed at 110° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 50mL of water was added. The resulting mixture was extracted with EtOAc(80 mL×3), and the combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=3/1) to give the title compound(4.21 g, 92%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 411.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.56-7.51 (m, 2H), 7.47-7.45 (m, 2H),7.22 (s, 1H), 5.38-5.29 (m, 1H), 5.25-5.17 (m, 1H), 4.13-4.07, 3.62-3.39(m, m, 1H), 3.68-3.58 (m, 1H), 2.68-2.38 (m, 2H), 1.38 (s, 9H).

Step 5) the Preparation of Compound 9-6

A mixture of compound 9-5 (2.0 g, 4.87 mmol), compound 1-14-2 (1.26 g,4.97 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (70 mg, 0.10 mmol) and KOAc (1.19 g, 12.2mmol) in DMF (20 mL) was stirred at 90° C. under N₂ for 2.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (100 mL) and filtered through a celite pad. Water (30 mL) wasadded to the filtrate, and the resulting mixture was extracted withEtOAc (40 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound (1.43 g, 64%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 458.4 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.81-7.79 (m, 2H), 7.65-7.60 (m, 2H),7.28 (s, 1H), 5.39-5.26 (m, 1H), 5.20-5.12 (m, 1H), 4.07-3.99, 3.59-3.41(m, 1H), 3.69-3.62 (m, 1H), 2.62-2.51 (m, 2H), 1.34 (s, 12H), 1.28 (s,9H).

Step 6) the Preparation of Compound 9-7

To a solution of compound 9-6 (4.57 g, 10 mmol) in EtOAc (20.0 mL) wasadded a solution of HCl in EtOAc (20 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the reaction mixture was concentrated in vacuo,and EtOAc (30 mL) was added. The mixture was stirred and pulped, thenfiltered to give the title compound as a pale yellow solid (3.04 g,85%), which was used for the next step without further purification. Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 358.6 [M+H]⁺.

Step 7) the Preparation of Compound 9-8

A suspension of compound 9-7 (6.88 g, 19.26 mmol), compound 1-13-2 (5.06g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) was stirredat 0° C., then DIPEA (21.0 mL) was added dropwise. At the end of theaddition, the mixture was stirred at rt for 3.0 hrs. After the reactionwas completed, the mixture was diluted with water (100 mL). The aqueouslayer was extracted with DCM (100 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound as a solid (6.44 g,65%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 515.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H),7.26 (s, 1H), 5.56, 5.55 (d, d, 1H), 5.32-5.24 (m, 0.5H), 5.19-5.11 (m,0.5H), 4.91-4.87 (m, 1H), 4.30-4.25 (m, 1H), 4.13-4.01 (m, 1H),3.75-3.69 (m, 1H), 3.66 (s, 3H), 2.93-2.77 (m, 1H), 2.29-2.15 (m, 2H),1.35 (q, 6H), 1.32 (q, 6H), 1.02, 1.00 (m, m, 3H), 0.95, 0.91 (m, m,6H).

Step 8) the Preparation of Compound 9-9

To a mixture of compound 8-4 (3.85 g, 7.98 mmol), compound 9-8 (3.42 g,6.65 mmol), Pd(PPh₃)₄ (0.77 g, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9 mmol)were added DME (50.0 mL) and pure water (10.0 mL) via syringe under N₂.The mixture was stirred at 90° C. for 3.0 hrs. After the reaction wascompleted, the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (150 mL), and then washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=100/1) to give the title compound as a beige solid (3.83 g, 80%).The compound was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.71-7.66 (m, 4H), 7.41 (s, 1H), 7.25,7.23 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.56, 5.55 (d, d, 1H),5.32-5.24 (m, 0.5H), 5.19-5.11 (m, 0.5H), 4.91-4.87 (m, 1H), 4.30-4.25(m, 1H), 4.13-4.01 (m, 1H), 3.75-3.67 (m, 1H), 3.66 (s, 3H), 2.93-2.84(m, 1H), 2.82-2.77 (m, 2H), 2.72-2.69 (m, 2H), 2.29-2.15 (m, 2H),1.77-1.65 (m, 4H), 1.57-1.49 (m, 4H), 1.29-1.21 (m, 2H), 1.02, 1.00 (m,m, 3H), 0.93, 0.92 (m, m, 6H).

Step 9) the Preparation of Compound 9-10

To a solution of compound 9-3 (5.94 g, 25.5 mmol) in EtOAc (30.0 mL) wasadded a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8 hrs. After thereaction was completed, the reaction mixture was concentrated in vacuo,and EtOAc (30 mL) was added. The mixture was stirred and pulped, thenfiltered to give the title compound as a pale yellow solid (3.05 g,90%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 134.5 [M+H]⁺

Step 10) the Preparation of Compound 9-11

A suspension of compound 9-10 (2.56 g, 19.26 mmol), compound 1-13-2(5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) wasstirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end ofthe addition, the mixture was stirred at rt for 3.0 hrs. After thereaction was completed, the mixture was diluted with DCM (200 mL),washed with NH₄Cl aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound asa solid (4.47 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 291.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.32-5.24 (m, 1.5H), 5.19-5.11 (m,0.5H), 4.73-4.68 (m, 1H), 4.41-4.36 (m, 1H), 3.94-3.81 (m, 1H), 3.63 (s,3H), 3.61-3.49 (m, 1H), 2.78-2.62 (m, 1H), 2.29-2.08 (m, 2H), 0.97, 0.95(m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 11) the Preparation of Compound 9-12

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 9-11 (3.04g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL), and then washed with water and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the titlecompound as colorless slurry (0.85 g, 25%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 487.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H),6.39 (s, 2H), 5.56-5.55 (d, d, 1H), 5.29-5.20 (m, 0.5H), 5.16-5.08 (m,0.5H), 4.41-4.35 (m, 1H), 4.31-4.27 (m, 1H), 3.88-3.76 (m, 1H), 3.66 (s,3H), 3.57-3.44 (m, 1H), 2.87-2.72 (m, 1H), 2.37-2.10 (m, 2H), 1.02, 1.00(m, m, 3H), 0.93, 0.91 (m, m, 3H).

Step 12) the Preparation of Compound 9-13

To a solution of compound 9-12 (0.62 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of addition, the mixture was stirred at rt for 5.0 hrs. Afterthe reaction was completed, the solvent THF was removed. The residue wasdissolved in EtOAc (50 mL), washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/3) to give the title compound asa white solid (0.54 g, 90%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 469.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78 (m, 1H), 7.77, 7.74 (d, d, 1H),7.72, 7.70 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.33-5.26 (m, 1.5H),4.99-4.93 (m, 1H), 4.34-4.29 (m, 1H), 3.93-3.81 (m, 1H), 3.63 (s, 3H),3.57-3.44 (m, 1H), 2.89-2.72 (m, 1H), 2.32-2.17 (m, 1H), 2.06-1.94 (m,1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 13) the Preparation of Compound 9-14

A suspension of compound 9-13 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc (0.11 g,1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (20 mL) and filtered through a celite pad. The filtrate waswashed with water (10 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a paleyellow solid (0.19 g, 82.9%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 517.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.79-7.78 (m,1H), 7.47, 7.45 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.34-5.26 (m, 1.5H),5.00-4.93 (m, 1H), 4.34-4.29 (m, 1H), 3.93-3.81 (m, 1H), 3.63 (s, 3H),3.57-3.44 (m, 1H), 2.89-2.72 (m, 1H), 2.32-2.17 (m, 1H), 2.06-1.94 (m,1H), 1.32, 1.29 (m, m, 12H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m,3H).

Step 14) the Preparation of Compound 9-15

A mixture of compound 9-14 (0.12 g, 0.23 mmol), compound 9-9 (0.17 g,0.23 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and K₂CO₃ (60 mg, 0.44 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 4.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/25) to give the title compound as apale yellow solid (99.4 mg, 45%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 481.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.74-7.67 (m, 4H), 7.52, 7.50 (d, d, 1H), 7.49, 7.47 (d, d, 1H),7.43-7.40 (m, 2H), 5.56, 5.55 (d, d, 1H), 5.46-5.39 (m, 0.5H), 5.34-5.24(m, 2H), 5.19-5.07 (m, 1.5H), 4.91-4.87 (m, 1H), 4.34-4.25 (m, 2H),4.13-4.01 (m, 1H), 3.93-3.81 (m, 1H), 3.75-3.68 (m, 1H), 3.66 (s, 3H),3.63 (s, 3H), 3.57-3.44 (m, 1H), 2.93-2.68 (m, 6H), 2.29-2.15 (m, 3H),2.06-1.96 (m, 1H), 1.72-1.60 (m, 4H), 1.55-1.48 (m, 4H), 1.29-1.21 (m,2H), 1.02-0.89 (m, 12H).

Example 10

Synthetic Route:

Step 1) the Preparation of Compound 10-2

To a solution of compound 10-1 (10 g, 77.5 mmol) in MeOH (50.0 mL) wasadded thionyl chloride (5.5 mL, 75.8 mmol) dropwise at 0° C. At the endof the addition, the mixture was stirred at 0° C. for 1.0 hr and then atrt for another 2.0 hrs. After the reaction was completed, NaHCO₃ aqueoussolution (50 mL) was added to the mixture, and the solvent MeOH wasremoved. To the residue was added water (30 mL), and the resultingmixture was extracted with CH₂Cl₂ (35 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(EtOAc) to give the title compound as colorless liquid (7.5 g, 67.6%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 144.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.38 (br, 1H), 4.20-4.16 (m, 1H), 3.67(s, 3H), 2.39-2.23 (m, 3H), 2.14-2.07 (m, 1H).

Step 2) the Preparation of Compound 10-3

To a solution of compound 10-2 (6.45 g, 45.06 mmol) in MeCN (30.0 mL)was added DMAP (0.55 g, 4.5 mmol) at 0° C., followed by di-tert-butyldicarbonate (10.82 g, 49.56 mmol) dropwise, and the mixture was stirredat 0° C. for 30 mins and then at rt for another 2.0 hrs. After thereaction was completed, the mixture was concentrated in vacuo, theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/1) to give the title compound as colorless liquid (5.0 g,45.6%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 144.2 [M−Boc]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.60-4.57 (m, 1H), 3.75 (s, 3H),2.65-2.55 (m, 1H), 2.50-2.42 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.96 (m,1H), 1.45 (s, 9H).

Step 3) the Preparation of Compound 10-4

To a solution of compound 10-3 (3.74 g, 15.4 mmol) in toluene (50.0 mL)was added lithium triethylborohydride dropwise (1.79 g, 16.9 mmol) at−78° C. After the mixture was stirred at −78° C. for 70 mins, DIPEA (3.2mL, 19.4 mmol), DMAP (0.19 g, 1.54 mmol) and TFAA (3.0 mL, 40.4 mmol)were added in turn, and then the mixture was stirred at rt for 2.0 hrs.After the reaction was completed, the mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as yellow liquid (2.26 g, 64.8%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 128.2 [M−Boc]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.65-6.52 (br, 1H), 4.96-4.91 (br, 1H),4.68-4.57 (m, 1H), 3.76 (s, 3H), 3.12-3.00 (m, 1H), 2.71-2.61 (m, 1H),1.49-1.44 (br, 9H).

Step 4) the Preparation of Compound 10-5

To a solution of diethylzinc (0.49 g, 3.94 mmol) in toluene (6.0 mL) wasadded chloroiodomethane (1.39 g, 7.9 mmol) at 0° C. After the mixturewas stirred at 0° C. for 45 mins, a solution of compound 10-4 (0.3 g,1.32 mmol) in toluene (4.0 mL) was added, and then the mixture wasstirred at 0° C. for 18 hrs. After the reaction was completed, themixture was quenched with saturated NH₄Cl aqueous solution (15 mL). Theresulting mixture was extracted with EtOAc (25 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=10/1) to give the title compound as yellow liquid (0.19g, 59.7%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 142.2 [M−Boc]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.64-4.51 (m, 1H), 3.70 (s, 3H),3.56-3.45 (m, 1H), 2.64-2.54 (m, 1H), 2.05-2.01 (m, 1H), 1.50, 1.41 (s,s, 9H), 0.75-0.65 (m, 3H).

Step 5) the Preparation of Compound 10-6

To a solution of compound 10-5 (1.02 g, 4.23 mmol) in THF (20.0 mL) wasadded lithium hydroxide monohydrate aqueous solution (0.89 g, 21.2 mmol,10 mL) at 0° C., and the mixture was stirred at 40° C. for 12 hrs. Afterthe reaction was completed, THF was removed and 10 mL of water was addedto the mixture. The resulting mixture was extracted with EtOAc (25mL×3), and then the aqueous phase was adjusted to pH 1 with hydrochloricacid (10%) and extracted with EtOAc (25 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo togive the title compound as a white solid (0.84 g, 87%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, neg.ion) m/z: 226.2 [M−H]⁻; and

¹H NMR (400 MHz, CD₃OD) δ (ppm): 4.53-4.46 (m, 1H), 3.48-3.42 (m, 1H),2.70-2.57 (m, 1H), 2.05-2.01 (m, 1H), 1.60-1.54 (m, 1H), 1.48, 1.41 (s,s, 9H), 0.89-0.80 (m, 1H), 0.73-0.66 (m, 1H).

Step 6) the Preparation of Compound 10-7

To a solution of compound 10-6 (5.79 g, 25.5 mmol) in EtOAc (30.0 mL)was added a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the endof the addition, the mixture was stirred at rt for 8 hrs. After thereaction was completed, the reaction mixture was concentrated in vacuo,and EtOAc (30 mL) was added. The mixture was stirred and pulped, thenfiltered to give the title compound as a pale yellow solid (2.92 g,90%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 128.5 [M+H]⁺.

Step 7) the Preparation of Compound 10-8

A suspension of compound 10-7 (2.45 g, 19.26 mmol), compound 1-13-2(5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) wasstirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end ofthe addition, the mixture was stirred at rt for 3.0 hrs. After thereaction was completed, the mixture was diluted with DCM (100 mL),washed with NH₄Cl aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound asa solid (4.38 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 285.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.56, 5.55 (d, d, 1H), 4.40-4.37 (m,1H), 4.05-4.01 (m, 1H), 3.66 (s, 3H), 3.33-3.27 (m, 1H), 2.29-2.15 (m,2H), 1.91-1.85 (m, 1H), 1.48-1.40 (m, 1H), 1.02, 1.00 (m, m, 3H),0.94-0.88 (m, 4H), 0.49-0.45 (m, 1H).

Step 8) the Preparation of Compound 10-9

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 10-8 (2.97g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL), and then washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound as colorless slurry (0.67 g, 20%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 481.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H),6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.42-4.38 (m, 1H), 4.09-4.05 (m,1H), 3.66 (s, 3H), 3.41-3.35 (m, 1H), 2.45-2.38 (m, 1H), 2.21-2.09 (m,1H), 2.08-2.03 (m, 1H), 1.45-1.37 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H), 0.88-0.83 (m, 1H), 0.43-0.40 (m, 1H).

Step 9) the Preparation of Compound 10-10

A solution of compound 10-9 (0.61 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.After the reaction was completed, the solvent THF was removed, and thenthe residue was dissolved in EtOAc (50 mL). The combined organic phasewere washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/3) to give the title compound as awhite solid (0.50 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 463.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.79 (m, 1H), 7.77-7.74 (d, d,1H), 7.72, 7.70 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 4.84-4.80 (m, 1H),4.35-4.31 (m, 1H), 3.63 (s, 3H), 3.30-3.23 (m, 1H), 2.46-2.38 (m, 1H),2.07-1.94 (m, 2H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89(m, m, 3H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H).

Step 10) the Preparation of Compound 10-11

A suspension of compound 10-10 (0.21 g, 0.44 mmol), compound 1-14-2(0.13 g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and anhydrousKOAc (0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂for 3.0 hrs. After the reaction was completed, the mixture was cooled tort, diluted with EtOAc (20 mL) and filtered through a celite pad. Thefiltrate was washed with water (10 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/3) to give the title compound asa pale yellow solid (0.19 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 511.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13-8.11 (d, d, 1H), 7.80-7.79 (m,1H), 7.47-7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 4.85-4.81 (m, 1H),4.35-4.31 (m, 1H), 3.63 (s, 3H), 3.30-3.23 (m, 1H), 2.46-2.38 (m, 1H),2.07-1.94 (m, 2H), 1.49-1.42 (m, 1H), 1.32, 1.29 (m, m, 12H), 0.97, 0.95(m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H).

Step 11) the Preparation of Compound 10-12

To a solution of compound 8-2 (2.75 g, 14.34 mmol) and compound 10-0(5.23 g, 21.51 mmol) in DMF (15.0 mL) was added NaH (60%, 1.43 g, 35.85mmol) at 0° C. under N₂. At the end of the addition, the mixture wasstirred at 50° C. for 18 hrs. After the reaction was completed, themixture was cooled to rt and quenched with water (100 mL). The aqueousphase was extracted with EtOAc (100 mL×3). The combined organic layerswere washed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=8/1) to give the title compound (0.79 g,20%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 276.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.84, 6.82 (m, m, 1H), 6.77, 6.75 (m,m, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.81-2.79 (m, 2H), 2.73-2.65 (m,2H), 2.51-2.39 (m, 2H), 2.35-2.34 (m, 3H), 1.84-1.74 (m, 4H).

Step 12) the Preparation of Compound 10-13

To a suspension of compound 10-12 (1.05 g, 3.8 mmol) and triethylsilane(3.7 mL, 23 mmol) was added TFA (8.0 mL) dropwise at 0° C. under N₂. Atthe end of the addition, the mixture was stirred at 40° C. for 7.0 hrs.After the reaction was completed, the solvent TFA was removed, and thenthe residue was dissolved in EtOAc (50 mL). The resulting mixture waswashed with Na₂CO₃ aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=5/1) to give the title compound(0.84 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 262.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.62-6.61 (m, 2H), 3.77 (s, 6H),2.77-2.69 (m, 6H), 2.56-2.45 (m, 2H), 2.30-2.29 (m, 3H), 1.89-1.79 (m,4H).

Step 13) the Preparation of Compound 10-14

To a solution of compound 10-13 (1.12 g, 4.3 mmol) in glacial aceticacid (40.0 mL) was added hydrogen bromide (9.6 mL, 85 mmol) dropwise. Atthe end of the addition, the mixture was refluxed for 12 hrs. After thereaction was completed, the mixture was quenched with saturated NaHCO₃aqueous solution (50 mL). The aqueous layer was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the titlecompound as a white solid (0.45 g, 45%). The compound was characterizedby the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.45 (m, 2H), 4.97 (brs, 2H), 2.81-2.69(m, 6H), 2.60-2.48 (m, 2H), 2.30-2.29 (m, 3H), 1.91-1.81 (m, 4H).

Step 14) the Preparation of Compound 10-15

To a solution of compound 10-14 (0.35 g, 1.5 mmol) in DCM (20.0 mL) wasadded trifluoromethanesulfonic anhydride (1.2 mL, 7.1 mmol) dropwise at0° C. Triethylamine (2.4 mL, 17.27 mmol) was then added slowly, and themixture was stirred at rt for 2.0 hrs. After the reaction was completed,the mixture was quenched with ice water (20 mL). The aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound (0.56 g, 75%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.28 (m, 2H), 2.79-2.69 (m, 6H),2.56-2.44 (m, 2H), 2.30-2.29 (m, 3H), 2.04-1.92 (m, 4H).

Step 15) the Preparation of Compound 10-16

To a mixture of compound 10-15 (3.31 g, 6.65 mmol), compound 1-15 (3.3g, 6.65 mmol), Pd(PPh₃)₄ (0.77 g, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9mmol) were added DME (50.0 mL) and H₂O (10.0 mL) via syringe. Themixture was stirred at 90° C. under N₂ for 3.0 hrs. After the reactionwas completed, the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (150 mL). The resulting mixture was washed with water(50 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=100/1) to give the title compound as a beige solid (3.1g, 65%). The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H),7.25, 7.22 (d, d, 1H), 7.02, 7.00 (d, d, 1H), 5.32, 5.29 (d, d, 1H),5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.65 (m,1H), 3.63 (s, 3H), 2.83-2.81 (m, 2H), 2.77-2.69 (m, 4H), 2.56-2.44 (m,2H), 2.30-2.29 (m, 3H), 2.26-1.96 (m, 9H), 0.97, 0.95 (m, m, 3H),0.90-0.89 (m, m, 3H).

Step 16) the Preparation of Compound 10-17

A mixture of compound 10-16 (0.16 g, 0.23 mmol), compound 10-11 (0.12 g,0.23 mmol), Pd(PPh₃)₄ (30 mg, 0.03 mmol) and K₂CO₃ (60 mg, 0.44 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 4.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wasdiluted with EtOAc (50 mL), and washed with water (20 mL×3) and brine.The organic layer was dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(MeOH/DCM (v/v)=1/25) to give the title compound as a pale yellow solid(98.48 mg, 45%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 476.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.92-7.87 (m, 2H), 7.60-7.56 (m, 5H),7.52-7.49 (m, 2H), 6.72-6.71 (m, 1H), 5.32, 5.30 (m, m, 2H), 5.23-5.19(m, 1H), 4.83-4.80 (m, 1H), 4.41-4.31 (m, 2H), 3.85-3.78 (m, 1H),3.69-3.65 (m, 1H), 3.63 (s, 6H), 3.30-3.23 (m, 1H), 3.02-2.98 (m, 2H),2.89-2.85 (m, 2H), 2.76-2.68 (m, 2H), 2.55-2.38 (m, 3H), 2.30-2.29 (m,3H), 2.27-1.85 (m, 11H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m, m, 6H), 0.90,0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H).

Example 11

Synthetic Route:

Step 1) the Preparation of Compound 11-2

To a solution of N,N,N′,N′-tetramethylethylenediamine (40.0 mL) inhexane (100 mL) were added 1,2-dimethoxybenzene (40.0 g, 0.29 mol) andn-BuLi (1.6 M in hexane, 200 mL, 0.32 mol) dropwise in turn. At the endof the addition, the mixture was stirred at rt for 28 hrs. After coolingto −78° C., ClSiMe₃ (45.0 mL) was added dropwise to the mixture. At theend of the addition, the reaction was stirred at rt. After the reactionwas completed, the mixture was quenched with water (100 mL). The aqueouslayer was extracted with hexane (100 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(hexane/DCM (v/v)=10/1) to give the title compound as colorless oil(51.5 g, 85%). The compound was characterized by the followingspectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.06-7.02 (m, 1H), 6.97-6.93 (m, 2H),3.86 (s, 6H), 0.28 (s, 9H).

Step 2) the preparation of compound 11-3 To a solution of compound 11-2(69.34 g, 0.33 mol) in N,N,N′,N′-tetramethylethylenediamine (60.0 mL)was added n-BuLi (1.6 M in hexane, 250 mL, 0.40 mol) dropwise at 0° C.At the end of the addition, the mixture was stirred at rt for 25 hrs.After cooling to −78° C., ClSiMe₃ (60.0 mL) was added dropwise to themixture. At the end of the addition, the reaction was stirred at rt.After the reaction was completed, the mixture was quenched with icewater (150 mL). The aqueous layer was extracted with hexane (100 mL×3).

The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (hexane/DCM (v/v)=10/1) to give the title compoundas colorless oil (82.86 g, 89%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.11 (s, 2H), 3.83 (s, 6H), 0.29 (s,18H).

Step 3) the Preparation of Compound 11-4

To a solution of compound 11-3 (19.2 g, 68.1 mmol) in DCM (100 mL) wasadded a solution of ICl (23.1 g, 0.14 mol) in DCM (100 mL) dropwise at0° C. At the end of addition, the mixture was stirred at rt for 30 mins.After the reaction was completed, the mixture was quenched withsaturated sodium thiosulfate aqueous solution (100 mL). The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by a silica gel columnchromatography (hexane/DCM (v/v)=10/1) to give the title compound as apale yellow solid (21.5 g, 81%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.24 (s, 2H), 3.87 (s, 6H).

Step 4) the Preparation of Compound 11-5

To a solution of compound 11-4 (1.80 g, 4.62 mmol) in DCM (20.0 mL) wasadded boron tribromide (2.0 mL, 21.2 mmol) dropwise at −78° C. At theend of the addition, the mixture was stirred at −78° C. for 10 mins, andthen stirred at rt for another 1.0 hr. After the reaction was completed,the mixture was quenched with ice water (50 mL). The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM) to givethe title compound as a white solid (1.5 g, 90%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.00 (s, 2H), 5.66 (s, 2H).

Step 5) the Preparation of Compound 11-6

A solution of compound 11-5 (0.36 g, 1.0 mmol), cyclopentanone (0.25 g,3.0 mmol) and p-toluenesulfonic acid (19 mg, 0.1 mmol) in hexane (20.0mL) was refluxed for 5.0 hrs. After the reaction was completed, themixture was quenched with water (25 mL). The aqueous layer was extractedwith EtOAc (20 mL×3). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (hexane/DCM(v/v)=1/1) to give the title compound (0.20 g, 46%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.84 (s, 1H), 2.17 (m, 4H), 1.87 (m,4H).

Step 6) the Preparation of Compound 11-7

A mixture of compound 11-6 (4.28 g, 10 mmol), compound 1-15 (4.96 g, 10mmol), Pd(PPh₃)₄ (1.16 g, 1.0 mmol) and K₂CO₃ (3.45 g, 25 mmol) in themixed solvent of DME/H₂O (v/v=3/1, 40.0 mL) was stirred at 90° C. underN₂ for 3.0 hrs. After the reaction was completed, the mixture wasdiluted with water (50 mL). The aqueous layer was extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (MeOH/DCM (v/v)=1/100) togive the title compound as a pale yellow solid (3.35 g, 50%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 671.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.74, 7.71 (s, s, 1H), 7.60-7.56 (m,3H), 7.38-7.34 (m, 2H), 6.84, 6.82 (s, s, 1H), 5.32, 5.29 (d, d, 1H),5.23-5.19 (m, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.64 (m,1H), 3.63 (s, 3H), 2.30-1.77 (m, 13H), 0.97, 0.95 (m, m, 3H), 0.90-0.89(m, m, 3H).

Step 7) the Preparation of Compound 11-8

A mixture of compound 11-7 (3.35 g, 5.0 mmol), compound 10-11 (2.55 g,5.0 mmol), Pd(PPh₃)₄ (0.58 g, 0.5 mmol) and K₂CO₃ (1.73 g, 12.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 40.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (250 mL), and washed with water (100mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/25) to give the title compoundas a pale yellow solid (2.08 g, 45%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 464.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77 (m, 1H), 7.60-7.57 (m, 3H),7.54-7.51 (m, 2H), 7.43-7.40 (m, 2H), 7.36-7.32 (m, 2H), 5.32, 5.29 (d,d, 2H), 5.23-5.19 (m, 1H), 4.97-4.94 (m, 1H), 4.41-4.31 (m, 2H),3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.30-3.23 (m, 1H),2.45-2.38 (m, 1H), 2.30-1.74 (m, 15H), 1.49-1.42 (m, 1H), 0.97, 0.95 (m,m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.41-0.38 (m, 1H).

Example 12

Synthetic Route:

Step 1) the Preparation of Compound 12-1

To a solution of compound 8-2 (1.31 g, 6.82 mmol), compound 12-0 (1.64g, 7.15 mmol) and TEBAC (0.3 g, 1.36 mmol) in DMSO (30.0 mL) was addedsodium hydroxide aqueous solution (50%, 2.0 mL) at 0° C. At the end ofthe addition, the mixture was stirred at 50° C. for 2.0 hrs. After thereaction was completed, 50 mL of water was added to the mixture, and theresulting mixture was extracted with EtOAc (50 mL×3). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE) to give the title compound as yellow oil (1.07 g,60%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 263.5 [M+H]⁺; and

¹H NMR (400 MHz, d₆-DMSO) δ (ppm): 6.84, 6.82 (m, m, 1H), 6.77, 6.75 (m,m, 1H), 3.97-3.90 (m, 2H), 3.84 (d, 3H), 3.81 (d, 3H), 3.70-3.62 (m,2H), 2.83-2.81 (m, 2H), 2.01-1.93 (m, 2H), 1.80-1.71 (m, 2H).

Step 2) the Preparation of Compound 12-2

To a suspension of compound 12-1 (1.0 g, 3.8 mmol) and triethylsilane(3.7 mL, 23 mmol) was added TFA (8.0 mL) dropwise at 0° C. At the end ofthe addition, the mixture was stirred at 40° C. for 7.0 hrs. After thereaction was completed, the mixture was concentrated in vacuo. Theresidue was dissolved in EtOAc (50 mL). The resulting mixture was washedwith Na₂CO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=5/1) to give the title compound as paleyellow oil (0.80 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 249.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.67-6.66 (m, 2H), 3.77 (d, 6H),3.71-3.66 (m, 4H), 2.77-2.74 (m, 4H), 1.76-1.70 (m, 4H).

Step 3) the Preparation of Compound 12-3

To a solution of compound 12-2 (0.69 g, 2.77 mmol) in DCM (20.0 mL) wasadded boron tribromide (0.36 mL, 3.88 mmol) dropwise at −78° C. At theend of the addition, the mixture was stirred at −78° C. for 10 mins, andthen stirred at rt for another 1.0 hr. After the reaction was completed,the mixture was quenched with ice water (20 mL). The aqueous layer wasextracted with DCM (25 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=12/1) to give the title compound as colorless liquid (0.61 g,100%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 221.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.45 (m, 2H), 4.97 (brs, 2H), 3.74-3.70(m, 4H), 2.75-2.72 (m, 4H), 1.79-1.72 (m, 4H).

Step 4) the Preparation of Compound 12-4

To a solution of compound 12-3 (1.70 g, 7.7 mmol) in DCM (50.0 mL) wasadded pyridine (3.1 mL, 38.6 mmol) dropwise at 0° C. under N₂. After themixture was stirred for 10 mins, trifluoromethanesulfonic anhydride (3.9mL, 23.1 mmol) was added, and then the mixture was stirred at rt for 1.0hr. After the reaction was completed, the mixture was quenched with icewater (50 mL). The aqueous layer was extracted with DCM (60 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=8/1) to give the title compound aspale yellow oil (3.17 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 485.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.28 (m, 2H), 3.71-3.66 (m, 4H),2.78-2.76 (m, 4H), 1.90-1.84 (m, 4H).

Step 5) the Preparation of Compound 12-6

To a solution of compound 12-5 (6.86 g, 27.97 mmol) in DCM (70.0 mL) wasadded Dess-Martin periodinane (23.7 g, 56 mmol) in portions at 0° C. Atthe end of the addition, the mixture was stirred at rt for 7.0 hrs.After the mixture was completed, the reaction was quenched with Na₂S₂O₃aqueous solution (100 mL), and the mixture was filtered through a celitepad. The filtrate was extracted with DCM (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=6/1) to give the title compound as pale yellow liquid(5.78 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 244.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.49-4.45 (m, 1H), 4.05, 4.00 (m, m,1H), 3.88, 3.84 (m, m, 1H), 3.79 (s, 3H), 3.19-3.12 (m, 1H), 2.72-2.65(m, 1H), 1.43 (s, 9H).

Step 6) the Preparation of Compound 12-7

To a solution of compound 12-6 (5.81 g, 23.9 mmol) in DCM (70.0 mL) wasadded Et₂NF₃ (4.85 mL, 35.9 mmol) dropwise at −78° C. At the end of theaddition, the mixture was stirred at −78° C. for 2.0 hrs and then at rtfor another 19 hrs. After the reaction was completed, the mixture wasquenched with NH₄Cl aqueous solution (50 mL), and the resulting mixturewas extracted with DCM (60 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=20/1) to give the title compound as pale yellow liquid(5.0 g, 79%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 266.25 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.68-4.63 (m, 1H), 4.01-3.87 (m, 1H),3.78 (s, 3H), 3.75-3.63 (m, 1H), 2.84-2.66 (m, 1H), 2.51-2.31 (m, 1H),1.43 (d, 9H, J=16 Hz).

Step 7) the Preparation of Compound 12-8

To a solution of compound 12-7 (5.0 g, 18.86 mmol) in THF (40.0 mL) wasadded LiOH aqueous solution (1.5 g, 20 mL) at 0° C., and the mixture wasstirred at rt for 2.0 hrs. After the reaction was completed, the mixturewas adjusted to pH 5 with diluted hydrochloric acid (1 M), and thesolvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2with diluted hydrochloric acid (1 M). The resulting mixture wasextracted with EtOAc (80 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and concentrated in vacuo to give the titlecompound as a white solid (4.45 g, 94%). The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 252.23 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.60 (brs, 1H), 4.94-4.72, 4.60-4.57(m, m, 1H), 3.89-3.74 (m, 2H), 2.78-2.48 (m, 2H), 1.44 (d, 9H, J=16 Hz).

Step 8) the Preparation of Compound 12-9

To a solution of compound 1-10 (2.41 g, 8.66 mmol) and compound 12-8(2.17 g, 8.66 mmol) in DCM (30 mL) was added TEA (2.5 mL, 17.32 mmol)dropwise at 0° C. At the end of the addition, the mixture was stirred atrt for 3.0 hrs. After the reaction was completed, the mixture wasquenched with water (50 mL), and the resulting mixture was extractedwith DCM (30 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo to give the title compound(3.6 g), which was used for the next step without further purification.The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 421.25 [M+H]⁺.

Step 9) the Preparation of Compound 12-10

A mixture of compound 12-9 (3.6 g, 8.6 mmol) and ammonium acetate (7.0g, 86 mmol) in toluene (30.0 mL) was refluxed at 110° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 60mL of water was added. The resulting mixture was extracted with EtOAc(80 mL×3), and the combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=6/1) to give the title compound(1.47 g, 40%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 429.27 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.54-7.52 (m, 2H), 7.48-7.46 (m, 2H),7.26-7.25 (m, 1H), 5.19-5.18 (m, 1H), 3.70-3.52 (m, 2H), 2.78-2.65 (m,2H), 1.48 (s, 9H).

Step 10) the Preparation of Compound 12-11

A mixture of compound 12-10 (1.4 g, 3.27 mmol), compound 1-14-2 (0.92 g,3.6 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.13 g, 1.16 mmol) and KOAc (0.81 g, 8.17mmol) in DME (25.0 mL) was stirred at 90° C. under N₂ for 2.0 hrs. Afterthe reaction was completed, the mixture was diluted with EtOAc (100 mL)and filtered through a celite pad. The filtrate was washed with water(50 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound (1.5 g, 96%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 476.34 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.54-7.52 (m, 2H), 7.48-7.46 (m, 2H),7.26-7.25 (m, 1H), 5.19-5.18 (m, 1H), 3.70-3.52 (m, 2H), 2.78-2.65 (m,2H), 1.48 (s, 9H), 1.35 (s, 12H).

Step 11) the Preparation of Compound 12-12

To a solution of compound 12-11 (5.75 g, 12.1 mmol) in EtOAc (40.0 mL)was added a solution of HCl in EtOAc (20.0 mL, 4 M) dropwise. At the endof the addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the reaction mixture was concentrated in vacuo,and EtOAc (50 mL) was added. The mixture was stirred and pulped, thenfiltered to give the title compound as a white solid (3.41 g, 75%),which was used for the next step without further purification. Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 376.1 [M+H]⁺.

Step 12) the Preparation of Compound 12-13

A suspension of compound 12-12 (0.98 g, 2.6 mmol), compound 1-13-2 (0.6g, 2.86 mmol) and EDCI (0.55 g, 2.86 mmol) in DCM (15.0 mL) was stirredat 0° C., then DIPEA (1.72 mL, 10.4 mmol) was added dropwise. At the endof the addition, the mixture was stirred at rt for 3.0 hrs. After thereaction was completed, the mixture was diluted with DCM (40 mL). Theresulting mixture was washed with NH₄Cl aqueous solution and brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound as a white solid (0.80 g, 58%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H),7.29 (s, 1H), 5.56, 5.55 (d, d, 1H), 5.10-5.05 (m, 1H), 4.32-4.28 (m,1H), 3.94-3.81 (m, 1H), 3.66 (s, 3H), 2.90-2.72 (m, 1H), 2.50-2.31 (m,1H), 2.28-2.16 (m, 1H), 1.35, 1.32 (m, m, 12H), 1.02, 1.00 (m, m, 3H),0.93, 0.91 (m, m, 3H).

Step 13) the Preparation of Compound 12-14

To a mixture of compound 12-13 (0.43 g, 0.81 mmol), compound 12-4 (0.39g, 0.81 mmol), Pd(PPh₃)₄ (47 mg, 0.04 mmol) and K₂CO₃ (0.29 g, 2.04mmol) were added DME (8.0 mL) and pure water (2.0 mL) via syringe. Themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was diluted with EtOAc (30 mL). The resultingmixture was washed with water (10 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOHc (v/v)=100/1) to give the title compoundas a white solid (0.33 g, 55%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 741.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.71-7.66 (m, 4H), 7.43 (s, 1H), 7.25,7.22 (d, d, 1H), 7.02, 7.00 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.10-5.05(m, 1H), 4.32-4.28 (m, 1H), 4.21-4.07 (m, 1H), 3.94-3.81 (m, 1H),3.70-3.65 (m, 7H), 2.91-2.72 (m, 5H), 2.50-2.30 (m, 1H), 2.28-2.16 (m,1H), 1.85-1.79 (m, 4H), 1.02, 1.00 (m, m, 3H), 0.94, 0.91 (m, m, 3H).

Step 14) the Preparation of Compound 12-15

To a solution of compound 12-8 (6.4 g, 25.5 mmol) in EtOAc (30.0 mL) wasadded a solution of HCl in EtOAc (30.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the mixture was concentrated in vacuo, and EtOAc(60.0 mL) was added. The mixture was stirred and pulped, then filteredto give the title compound as a pale yellow solid (3.47 g, 90%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 152.5 [M+H]⁺.

Step 15) the Preparation of Compound 12-16

A suspension of compound 12-15 (2.91 g, 19.26 mmol), compound 1-13-2(5.06 g, 28.88 mmol) and EDCI (5.56 g, 28.88 mmol) in DCM (100 mL) wasstirred at 0° C., then DIPEA (21.0 mL) was added dropwise. At the end ofthe addition, the mixture was stirred at rt for 3.0 hrs. After thereaction was completed, the mixture was diluted with DCM (200 mL),washed with NH₄Cl aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound asa solid (3.86 g, 65%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 309.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.56, 5.55 (d, d, 1H), 4.91-4.86 (m,1H), 4.25-4.21 (m, 1H), 4.06-3.93 (m, 1H), 3.82-3.68 (m, 1H), 3.66 (s,3H), 2.75-2.57 (m, 1H), 2.44-2.11 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H).

Step 16) the Preparation of Compound 12-17

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 12-16 (3.23g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL) and washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/2) to give the title compound ascolorless slurry (0.71 g, 20%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 505.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H),6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.57-4.52 (m, 1H), 4.32-4.28 (m,1H), 3.96-3.83 (m, 1H), 3.76-3.67 (m, 1H), 3.66 (s, 3H), 2.92-2.74 (m,1H), 2.63-2.43 (m, 1H), 2.20-2.08 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H).

Step 17) the Preparation of Compound 12-18

A solution of compound 12-17 (0.65 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.After the reaction was completed, the solvent THF was removed, and thenthe residue was dissolved in EtOAc (50 mL). The combined organic phasewere washed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.53g, 85%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 487.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.70 (m, 3H), 5.32, 5.29 (d, d,1H), 5.24-5.18 (m, 1H), 4.36-4.31 (m, 1H), 4.01-3.88 (m, 1H), 3.76-3.66(m, 1H), 3.63 (s, 3H), 2.96-2.78 (m, 1H), 2.64-2.43 (m, 1H), 2.05-1.93(m, 1H), 0.97-0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 18) the Preparation of Compound 12-19

A suspension of compound 12-18 (0.22 g, 0.44 mmol), compound 1-14-2(0.13 g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.049 mmol) and KOAc(0.11 g, 1.12 mmol) in DME (5.0 mL) was stirred at 90° C. under N₂ for3.0 hrs. After the reaction was completed, the mixture was cooled to rt,diluted with EtOAc (20 mL) and filtered through a celite pad. Thefiltrate was washed with water (10 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/3) to give the title compound asa pale yellow solid (0.19 g, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 535.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.77 (m, 1H),7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.25-5.20 (m, 1H),4.36-4.31 (m, 1H), 4.01-3.88 (m, 1H), 3.76-3.66 (m, 1H), 3.63 (s, 3H),2.96-2.78 (m, 1H), 2.64-2.43 (m, 1H), 2.05-1.93 (m, 1H), 1.32-1.29 (m,m, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 19) the Preparation of Compound 12-20

A mixture of compound 12-19 (0.53 g, 1.0 mmol), compound 12-14 (0.74 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/25) to give the title compoundas a pale yellow solid (0.40 g, 40%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 500.5 [M+2H]2; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.74-7.67 (m, 4H), 7.50-7.49, 7.48-7.47 (dd, dd, 1H), 7.46, 7.44(d, d, 1H), 7.43 (s, 1H), 7.42, 7.41 (dd, dd, 1H), 5.56, 5.55 (d, d,1H), 5.35-5.29 (m, 2H), 5.10-5.05 (m, 1H), 4.36-4.28 (m, 2H), 4.21-4.07(m, 1H), 4.00-3.72 (m, 3H), 3.69-3.65 (m, 7H), 3.63 (s, 3H), 2.94-2.72(m, 6H), 2.62-2.16 (m, 3H), 2.05-1.93 (m, 1H), 1.80-1.74 (m, 4H),1.02-0.89 (m, 12H).

Example 13

Synthetic Route:

Step 1) the Preparation of Compound 13-1

A mixture of compound 1-10 (4.0 g, 10.23 mol), compound 1-14-2 (2.86 g,11.25 mmol), Pd(dppf)Cl₂.CH₂C2 (0.42 g, 0.51 mmol) and KOAc (2.51 g,25.57 mmol) in DMF (40.0 mL) was stirred at EtOAc (250 mL) and filteredthrough a celite pad. The filtrate was washed with water (120 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound (3.6 g, 80%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.35 (m, 4H), 7.10 (s, 1H), 4.93 (t,1H, J=8.2 Hz), 3.88-3.66 (m, 2H), 2.90 (t, 1H, J=8.0 Hz), 2.50-2.47 (m,2H), 2.27-2.25 (m, 1H), 1.48 (s, 9H), 1.26 (s, 12H).

Step 2) the Preparation of Compound 13-2

To a mixture of compound 13-1 (2.92 g, 6.65 mmol), compound 1-8 (2.97 g,6.65 mmol), Pd(PPh₃)₄ (0.77 g, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9 mmol)were added DME (50.0 mL) and H₂O (10.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 3.0 hrs. After the reaction wascompleted, the solvent DME was removed. The residue was dissolved inEtOAc (150 mL). The resulting mixture was washed with water (50 mL×3)and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=100/1) to give the title compound as a pale yellow solid (2.52 g,60%). The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H),7.24-7.23, 7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 4.97-4.93 (m,1H), 3.64-3.58 (m, 1H), 3.31-3.23 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82(m, 2H), 2.47-2.38 (m, 1H), 2.29-2.16 (m, 1H), 2.10-1.97 (m, 2H),1.74-1.43 (m, 8H), 1.41 (s, 9H).

Step 3) the Preparation of Compound 13-3

To a solution of compound 5-4-2 (22.0 g, crude product) in dry THF (250mL), compound 1-19 (7.6 g, 35.5 mmol) and NaOH (1 M, 85.0 mmol) wereadded in turn. At the end of the addition, the mixture was stirred at rtfor 1.0 hr. After the reaction was completed, the mixture was extractedwith EtOAc (100 mL×3). The combined organic layers were washed with NaOHaqueous solution (1 M, 15 mL) and brine, dried over Na₂SO₄ andconcentrated in vacuo to give the title compound (17.0 g, 100%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 446.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.06 (br, 1H), 7.75 (d, 1H), 7.35, 7.33(d, d, 1H), 7.28-7.22 (m, 5H), 6.69, 6.67 (d, d, 1H), 5.68 (brs, 2H),5.14-5.13 (m, 2H), 4.29-4.25 (m, 1H), 3.66-3.60 (m, 1H), 3.45-3.37 (m,1H), 2.39-2.32 (m, 1H), 2.09-2.00 (m, 1H), 1.96-1.77 (m, 2H).

Step 4) the Preparation of Compound 13-4

A solution of compound 13-3 (17.0 g, 38.1 mmol) and KOH (34.0 mL, 10%aq) in EtOH (200 mL) was stirred at 80° C. for 3.0 hrs. After thereaction was completed, the mixture was cooled to 0° C. and neutralizedto pH 7 by carefully adding concentrated HCl. The resulting precipitatewas collected by filtration and washed with EtOAc/hexane (v/v=5/1) togive the title compound 13-4 (12.6 g, 77.0%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 428.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02, 8.01 (d, d, 1H), 7.65, 7.62 (d,d, 1H), 7.28-7.22 (m, 5H), 7.20, 7.18 (d, d, 1H), 5.14-5.13 (m, 2H),5.00-4.95 (m, 1H), 3.64-3.57 (m, 1H), 3.44-3.37 (m, 1H), 2.49-2.41 (m,1H), 2.36-2.26 (m, 1H), 2.02-1.93 (m, 1H), 1.91-1.81 (m, 1H).

Step 5) the Preparation of Compound 13-5

To a solution of compound 13-4 (3.43 g, 8.03 mmol) in EtOAc (40.0 mL)was added a catalytic amount of Pd/C (0.35 g), and then the mixture wasstirred at 40° C. under 10 atm of H₂ gas for 5.0 hrs. After the reactionwas completed, the mixture was filtered. The filtrate was concentratedin vacuo to give the title compound 13-5 (2.02 g, 86%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 294.5 [M+H]⁺.

Step 6) the Preparation of Compound 13-6

To a solution of compound 13-5 (1.32 g, 4.5 mmol) in MeCN (30.0 mL) wasadded DMAP (55.03 mg, 0.45 mmol) at 0° C., followed by di-tert-butyldicarbonate (1.1 g, 4.96 mmol) dropwise, and the mixture was stirred at0° C. for 30 mins and then at rt for another 2.0 hrs. After the reactionwas completed, the mixture was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) togive the title compound as colorless liquid (0.88 g, 50%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 394.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02-8.01 (dd, 1H), 7.65, 7.62 (d, d,1H), 7.20, 7.18 (d, d, 1H), 5.01-4.96 (m, 1H), 3.64-3.57 (m, 1H),3.46-3.39 (m, 1H), 2.51-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.04-1.95 (m,1H), 1.93-1.83 (m, 1H), 1.43 (s, 9H).

Step 7) the Preparation of Compound 13-7

A mixture of compound 13-6 (0.36 g, 0.91 mmol), compound 1-14-2 (0.46 g,1.82 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (71.0 mg, 0.09 mmol) and KOAc (0.27 g,2.73 mmol) in DMF (10.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (60 mL) and filtered through a celite pad. The filtrate waswashed with water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=2/1) to give the title compound (0.34 g,85%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 442.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.60-8.59 (m, 1H), 7.78, 7.76 (d, d,1H), 7.63, 7.61 (d, d, 1H), 5.01-4.96 (m, 1H), 3.64-3.57 (m, 1H),3.46-3.39 (m, 1H), 2.51-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.04-1.95 (m,1H), 1.93-1.83 (m, 1H), 1.43 (s, 9H), 1.23, 1.20 (m, m, 12H).

Step 8) the Preparation of Compound 13-8

To a mixture of compound 13-7 (1.16 g, 2.62 mmol), compound 13-2 (1.65g, 2.62 mmol), Pd(PPh₃)₄ (0.12 g, 0.10 mmol) and K₂CO₃ (0.90 g, 5.24mmol) were added DME (12.0 mL) and H₂O (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 3.0 hrs. After the reactionwas completed, the mixture was cooled to rt and diluted with EtOAc (50mL). The resulting mixture was washed with water (20 mL×3) and brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=80/1) togive the title compound as a white solid (1.36 g, 65%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 797.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.92, 7.90 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 5.01-4.92 (m, 2H), 3.65-3.57 (m, 2H), 3.46-3.39(m, 1H), 3.31-3.23 (m, 1H), 2.93-2.88 (m, 4H), 2.51-2.16 (m, 4H),2.10-1.83 (m, 4H), 1.70-1.49 (m, 6H), 1.43 (s, 9H), 1.41 (s, 9H),1.39-1.35 (m, 2H).

Step 9) the Preparation of Compound 13-9

To a solution of compound 13-8 (3.98 g, 5.0 mmol) in EtOAc (40.0 mL) wasadded a solution of HCl in EtOAc (15 mL, 4 M) dropwise, and the mixturewas stirred at rt for 8.0 hrs. After the reaction was completed, themixture was concentrated in vacuo, and EtOAc (50 mL) was added. Theresulting mixture was stirred and pulped, and then filtered to give thetitle compound as a white solid (2.60 g, 70%), which was used for thenext step without further purification. The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 597.5 [M+H]⁺.

Step 10) the Preparation of Compound 13-10

To a suspension of compound 13-9 (1.93 g, 2.6 mmol), compound 13-9-2(597.94 mg, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6mmol) in DCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at0° C. At the end of the addition, the mixture was stirred at rt for 3.0hrs. After the reaction was completed, the mixture was diluted with DCM(40 mL). The resulting mixture was washed with NH₄Cl aqueous solutionand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) togive the title compound as a white solid (1.27 g, 50%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 491.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 7.35-7.27 (m, 6H), 7.19-7.14 (m, 4H), 5.91,5.89 (s, 2H), 5.35-5.34, 5.33-5.32 (m, m, 1H), 5.22-5.21, 5.20 (m, m,1H), 5.18-5.13 (m, 1H), 5.09-5.04 (m, 1H), 3.91-3.84 (m, 1H), 3.75-3.67(m, 1H), 3.64 (s, 6H), 3.57-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.93-2.88(m, 4H), 2.51-1.85 (m, 8H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H).

Example 14

Synthetic Route:

Step 1) the Preparation of Compound 14-2

To a suspension of compound 13-9 (1.55 g, 2.6 mmol), compound 14-1 (0.42g, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6 mmol) inDCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at 0° C. Atthe end of the addition, the mixture was stirred at rt for 3.0 hrs.After the reaction was completed, the mixture was diluted with DCM (40mL). The resulting mixture was washed with NH₄Cl aqueous solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) togive the title compound as a white solid (1.11 g, 50%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 855.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 5.44, 5.42 (m, m, 2H), 5.12-5.05 (m, 2H),4.64-4.47 (m, 2H), 3.88-3.81 (m, 1H), 3.72-3.66 (m, 1H), 3.64 (s, 6H),3.63-3.60 (m, 1H), 3.30-3.22 (m, 1H), 2.93-2.88 (m, 4H), 2.53-2.44 (m,1H), 2.34-1.74 (m, 7H), 1.70-1.49 (m, 6H), 1.46-1.37 (m, 2H), 1.36, 1.34(d, d, 3H), 1.30, 1.29 (d, d, 3H).

Example 15

Synthetic Route:

Step 1) the Preparation of Compound 15-2

To a suspension of compound 13-9 (1.93 g, 2.6 mmol), compound 15-1 (0.62g, 2.86 mmol), EDCI (0.55 g, 2.86 mmol) and HOAT (0.36 g, 2.6 mmol) inDCM (15.0 mL) was added DIPEA (1.72 mL, 10.4 mmol) dropwise at 0° C. Atthe end of the addition, the mixture was stirred at rt for 3.0 hrs.After the reaction was completed, the mixture was diluted with DCM (40mL). The resulting mixture was washed with NH₄Cl aqueous solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) togive the title compound as a white solid (1.16 g, 45%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 496.27 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 5.21, 5.19 (d, d, 2H), 5.09-5.01 (m, 2H),4.47-4.41 (m, 1H), 4.35-4.29 (m, 1H), 3.86-3.80 (m, 1H), 3.70-3.65 (m,1H), 3.63 (s, 6H), 3.59-3.53 (m, 1H), 3.20-3.12 (m, 1H), 2.93-2.88 (m,4H), 2.43-1.06 (m, 38H).

Example 16

Synthetic Route:

Step 1) the Preparation of Compound 16-1

To a solution of L(−)-pipecolinic acid (10.0 g, 77.4 mmol) in MeOH (50mL) was added thionyl chloride (8.5 mL, 117.2 mmol) dropwise at 0° C. Atthe end of the addition, the mixture was stirred at 0° C. for 1.0 hr andthen at 70° C. for another 3.0 hrs. After the reaction was completed,the mixture was concentrated in vacuo to give the title compound as awhite solid (11.0 g, 79.1%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 144.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.02 (br, 1H), 4.00 (br, 1H), 3.85 (s,3H), 3.63 (br, 1H), 3.15 (br, 1H), 2.28 (m, 1H), 2.08 (m, 2H), 1.86 (m,2H), 1.63 (br, 1H).

Step 2) the Preparation of Compound 16-2

To a solution of compound 16-1 (1.0 g, 5.57 mmol), compound 1-13-2 (1.47g, 8.38 mmol) and EDCI (2.14 g, 11.17 mmol) in DCM (40.0 mL) was addedDIPEA (5.0 mL, 30.25 mmol) dropwise at 0° C. At the end of the addition,the mixture was stirred at rt for 3.0 hrs. After the reaction wascompleted, 40 mL of water was added to the mixture, and the resultingmixture was extracted with CH₂Cl₂ (35 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=2/1) to give the title compound as colorless liquid(1.337 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 301.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.32, 5.29 (d, d, 1H), 4.93-4.89 (m,1H), 4.31-4.26 (m, 1H), 3.70 (s, 3H), 3.67-3.64 (m, 1H), 3.63 (s, 3H),3.11-3.02 (m, 1H), 2.23-2.14 (m, 1H), 2.13-2.05 (m, 2H), 1.20-1.02 (m,4H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 3) the Preparation of Compound 16-3

To a solution of compound 16-2 (1.41 g, 4.7 mmol) in THF (40.0 mL) wasadded LiOH aqueous solution (0.99 g, 23.5 mmol, 20 mL) at 0° C. At theend of the addition, the mixture was stirred at 40° C. for 12 hrs. Afterthe reaction was completed, the solvent THF was removed. The residue wasadded water (50 mL), and then extracted with EtOAc (40 mL×3). Theaqueous layer was adjusted to pH 1 with diluted hydrochloric acid (10%)and extracted with EtOAc (35 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo to give the title compoundas a white solid (1.24 g, 92%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 287.5 [M+H]⁺.

Step 4) the Preparation of Compound 16-4

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 16-3 (2.99g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL), and then washed with water and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=1/2) to give the titlecompound as colorless slurry (0.84 g, 25%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 483.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.54, 7.52 (dd, dd,1H), 7.50, 7.48 (m, m, 1H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H),4.35-4.26 (m, 2H), 3.88-3.81 (m, 1H), 3.66 (s, 3H), 3.15-3.06 (m, 1H),2.25-2.13 (m, 2H), 1.91-1.79 (m, 1H), 1.54-1.35 (m, 2H), 1.16-1.04 (m,2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H).

Step 5) the Preparation of Compound 16-5

A solution of compound 16-4 (0.62 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.After the reaction was completed, the solvent THF was removed, and thendissolved in EtOAc (50 mL). The resulting mixture was washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/3) togive the title compound as a white solid (0.50 g, 85%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 465.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.70 (m, 3H), 5.46-5.40 (m, 1H),5.32, 5.29 (d, d, 1H), 4.28-4.23 (m, 1H), 3.63 (s, 3H), 3.34-3.26 (m,1H), 3.09-3.00 (m, 1H), 2.09-1.99 (m, 2H), 1.96-1.88 (m, 1H), 1.60-1.45(m, 2H), 1.12-0.98 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Step 6) the Preparation of Compound 16-6

A suspension of compound 16-5 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc (0.11 g,1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt anddiluted with EtOAc (20 mL). The filtrate was washed with water (20 mL×3)and brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/3) to give the title compound as a yellow solid (0.18 g, 80%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 513.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.80, 7.79 (m,1H), 7.47, 7.45 (d, d, 1H), 5.49-5.43 (m, 1H), 5.32, 5.29 (d, d, 1H),4.28-4.23 (m, 1H), 3.63 (s, 3H), 3.34-3.26 (m, 1H), 3.09-3.00 (m, 1H),2.09-1.99 (m, 1H), 1.97-1.88 (m, 2H), 1.60-1.45 (m, 2H), 1.32, 1.29 (m,m, 12H), 1.11-0.98 (m, 2H), 0.97, 0.95 (m, m, 6H).

Step 7) the Preparation of Compound 16-7

To a solution of compound 1-10 (3.0 g, 10.79 mmol) and compound 16-3(3.4 g, 11.87 mmol) in MeCN (30.0 mL) was added DIPEA (2.14 mL, 12.95mmol) dropwise at 0° C. At the end of the addition, the mixture wasstirred at rt for 3.0 hrs. After the reaction was completed, thereaction was quenched with ice water (50 mL), and the resulting mixturewas extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=10/1) to give the title compound as a white solid (4.68g, 90%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 483.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H),5.32, 5.29 (d, d, 1H), 5.28 (s, 2H), 5.07-5.01 (m, 1H), 4.33-4.29 (m,1H), 3.72-3.66 (m, 1H), 3.63 (s, 3H), 3.13-3.04 (m, 1H), 2.23-2.14 (m,1H), 2.13-2.04 (m, 2H), 1.20-1.00 (m, 4H), 0.97, 0.95 (m, m, 3H), 0.90,0.89 (m, m, 3H).

Step 8) the Preparation of Compound 16-8

A mixture of compound 16-7 (1.76 g, 3.64 mmol) and ammonium acetate (4.2g, 5.46 mmol) in xylene (30.0 mL) was refluxed at 120° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 50mL of water was added. The resulting mixture was extracted with EtOAc(50 mL×3), and the combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=4/1) to give the title compound asa yellow solid (1.43 g, 85%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 463.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.58 (s, 1H), 7.45-7.41 (m, 2H),7.29-7.26 (m, 2H), 5.32, 5.29 (d, d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35(m, 1H), 3.77-3.69 (m, 1H), 3.63 (s, 3H), 2.86-2.76 (m, 1H), 2.25-2.13(m, 1H), 2.02-1.93 (m, 1H), 1.82-1.70 (m, 1H), 1.67-1.49 (m, 2H),1.21-1.00 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 9) the Preparation of Compound 16-9

A mixture of compound 16-8 (4.73 g, 10.23 mmol), compound 1-14-2 (2.86g, 11.25 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.42 g, 0.51 mmol) and KOAc (2.51 g,25.57 mmol) in DMF (40.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (200 mL) and filtered through a celite pad. The filtrate waswashed with water (120 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a paleyellow solid (4.18 g, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 511.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.64-7.57 (m, 4H), 7.19 (s, 1H), 5.32,5.29 (d, d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35 (m, 1H), 3.77-3.69 (m,1H), 3.63 (s, 3H), 2.86-2.76 (m, 1H), 2.25-2.13 (m, 1H), 2.02-1.93 (m,1H), 1.82-1.69 (m, 1H), 1.67-1.49 (m, 2H), 1.35, 1.32 (m, m, 12H),1.21-0.99 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 10) the Preparation of Compound 16-10

To a mixture of compound 16-9 (413.34 mg, 0.81 mmol), compound 1-8(361.24 mg, 0.81 mmol), Pd(PPh₃)₄ (47 mg, 0.04 mmol) and K₂CO₃ (290 mg,2.04 mmol) were added DME (8.0 mL) and H₂O (2.0 mL) via syringe. Themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (30 mL). The resulting mixture was washed with water(10 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(DCM/MeOH (v/v)=100/1) to give the title compound as a white solid (0.34g, 60%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 703.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H),7.24-7.23, 7.22-7.21 (d, d, 1H), 7.03, 7.00 (dd, dd, 1H), 5.32, 5.29 (d,d, 1H), 4.78-4.72 (m, 1H), 4.40-4.35 (m, 1H), 3.77-3.69 (m, 1H), 3.63(s, 3H), 2.89-2.76 (m, 5H), 2.25-2.13 (m, 1H), 2.02-1.93 (m, 1H),1.82-1.42 (m, 11H), 1.21-1.00 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89(m, m, 3H).

Step 11) the Preparation of Compound 16-11

A mixture of compound 16-10 (0.70 g, 1.0 mmol), compound 16-6 (0.51 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/25) to give the title compound as apale yellow solid (0.47 g, 50%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 470.3 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.53-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.18-5.13 (m, 1H),4.78-4.72 (m, 1H), 4.39-4.35 (m, 1H), 4.28-4.24 (m, 1H), 3.77-3.69 (m,1H), 3.63 (s, 6H), 3.34-3.26 (m, 1H), 3.09-3.00 (m, 1H), 2.93-2.89 (m,4H), 2.86-2.76 (m, 1H), 2.25-1.35 (m, 18H), 1.21-0.99 (m, 4H), 0.97,0.95 (m, m, 6H), 0.91, 0.89 (m, m, 6H).

Example 17

Synthetic Route:

Step 1) the Preparation of Compound 17-2

To a solution of compound 17-1 (3.75 g, 13.1 mmol) and compound 1-10(3.63 g, 13.1 mmol) in DCM (40.0 mL) was added Et₃N (2.73 mL, 19.65mmol) dropwise at 0° C. At the end of the addition, the mixture wasstirred at rt for 2.0 hrs. After the reaction was completed, the mixturewas quenched with water (50 mL), and the resulting mixture was extractedwith DCM (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the titlecompound (5.35 g), which was used for the next step without furtherpurification. The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 455.5 [M+H]⁺.

Step 2) the Preparation of Compound 17-3

A mixture of compound 17-2 (3.72 g, 8.2 mmol) and ammonium acetate (5.1g, 66 mmol) in toluene (34 mL) was refluxed at 110° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 50mL of water was added. The resulting mixture was extracted with EtOAc(80 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=4/1) to give the title compound (3.22 g,85%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 463.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.63-7.60 (m, 2H), 7.49-7.45 (m, 2H),7.24 (s, 1H), 6.08, 6.05 (d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m,1H), 3.92-3.85 (m, 1H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.37-2.14 (m,3H), 1.71-1.63 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.94-0.90 (m, 6H).

Step 3) the Preparation of Compound 17-4

A mixture of compound 17-3 (3.19 g, 6.9 mmol), compound 1-14-2 (1.93 g,7.6 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.28 g, 0.34 mmol) and KOAc (1.7 g, 17.25mmol) in DME (30.0 mL) was stirred at 90° C. under N₂ for 2.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (200 mL) and filtered through a celite pad. The filtrate waswashed with water (50 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/2) to give the title compound as a paleyellow solid (3.10 g, 88%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 511.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H),7.46 (s, 1H), 6.08, 6.05 (d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m,1H), 3.92-3.85 (m, 1H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.37-2.14 (m,3H), 1.71-1.63 (m, 1H), 1.35, 1.32 (m, m, 12H), 1.02, 1.00 (m, m, 3H),0.94-0.90 (m, 6H).

Step 4) the Preparation of Compound 17-5

To a mixture of compound 17-4 (3.93 g, 7.7 mmol), compound 1-8 (3.43 g,7.7 mmol), Pd(PPh₃)₄ (0.45 g, 0.38 mmol) and K₂CO₃ (2.1 g, 15.4 mmol)were added DME (32.0 mL) and H₂O (8.0 mL) via syringe under N₂. Themixture was stirred at 90° C. for 3.0 hrs. After the reaction wascompleted, the mixture was cooled to rt, diluted with EtOAc (200 mL).The resulting mixture was washed with water (50 mL×3) and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) togive the title compound (3.79 g, 70%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 703.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.71-7.66 (m, 4H), 7.32 (s, 1H),7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 6.07, 6.05(d, d, 1H), 5.04-4.99 (m, 1H), 4.32-4.27 (m, 1H), 3.92-3.85 (m, 1H),3.65 (s, 3H), 3.61-3.54 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H),2.37-2.14 (m, 3H), 1.74-1.42 (m, 9H), 1.02, 1.00 (m, m, 3H), 0.94-0.90(m, 6H).

Step 5) the Preparation of Compound 17-6

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 17-1 (2.99g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL) and washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/2) to give the title compound ascolorless slurry (0.84 g, 25%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 483.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H),6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.36-4.27 (m, 2H), 3.66 (s, 3H),3.65-3.61 (m, 1H), 3.43-3.37 (m, 1H), 2.39-2.31 (m, 1H), 2.20-2.02 (m,2H), 1.89-1.79 (m, 1H), 1.02, 1.00 (m, m, 3H), 0.93-0.91 (m, 3H),0.89-0.86 (m, 3H).

Step 6) the Preparation of Compound 17-7

A solution of compound 17-6 (0.62 g, 1.28 mmol) in THF (10 mL) was addedlithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. At the endof the addition, the mixture was stirred at rt for 5.0 hrs. After thereaction was completed, the solvent THF was removed, and then theresidue was dissolved in EtOAc (50 mL). The combined organic phase werewashed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.50g, 85%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 465.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78 (q, 1H), 7.76, 7.74 (d, d, 1H),7.72, 7.70 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.04 (m, 1H),4.30-4.25 (m, 1H), 3.72-3.65 (m, 1H), 3.63 (s, 3H), 3.47-3.37 (m, 1H),2.40-2.20 (m, 2H), 2.05-1.92 (m, 1H), 1.80-1.71 (m, 1H), 0.97, 0.95 (m,m, 3H), 0.96-0.86 (m, 6H).

Step 7) the Preparation of Compound 17-8

A suspension of compound 17-7 (0.21 g, 0.44 mmol), compound 1-14-2 (0.13g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc (0.11 g,1.12 mmol) in DME (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt anddiluted with EtOAc (20 mL). The resulting mixture was washed with water(10 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid(0.18 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 513.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.79-7.78 (q,1H), 7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.04 (m, 1H),4.30-4.25 (m, 1H), 3.72-3.65 (m, 1H), 3.63 (s, 3H), 3.47-3.37 (m, 1H),2.40-2.20 (m, 2H), 2.05-1.92 (m, 1H), 1.80-1.71 (m, 1H), 1.32, 1.29 (q,q, 12H), 0.97, 0.95 (m, m, 3H), 0.96-0.86 (m, 6H).

Step 8) the Preparation of Compound 17-9

A mixture of compound 17-5 (0.70 g, 1.0 mmol), compound 17-8 (0.51 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/25) to give the title compoundas a pale yellow solid (0.42 g, 45%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 470.3 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 5.34-5.29 (m, 3H), 5.07-5.02 (m, 1H), 4.42-4.37(m, 1H), 4.30-4.25 (m, 1H), 3.92-3.85 (m, 1H), 3.72-3.67 (m, 1H), 3.63(s, 6H), 3.61-3.54 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.88 (m, 4H),2.38-2.11 (m, 5H), 2.05-1.94 (m, 1H), 1.78-1.49 (m, 8H), 1.45-1.35 (m,2H), 0.97, 0.95 (m, m, 6H), 0.93-0.86 (m, 12H).

Example 18

Synthetic Route:

Step 1) the Preparation of Compound 18-2

To a solution of compound 18-1 (1.34 g, 4.6 mmol) in THF (10.0 mL) wasadded LiOH aqueous solution (2.1 g, 50 mmol, 8.0 mL) at 0° C., and thenthe mixture was stirred at rt overnight. After the reaction wascompleted, the solvent THF was removed. The residue was diluted withwater (50 mL) and extracted with EtOAc (20 mL×3). The aqueous layer wasadjusted to pH 2 with diluted hydrochloric acid (10%) and extracted withEtOAc (50 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo to give the title compound as colorless slurry(1.08 g, 85%). The compound was characterized by the followingspectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.26 (m, 5H), 5.13-5.12 (m, 2H),4.37-4.34 (m, 1H), 3.30-3.26 (m, 1H), 3.24-3.17 (m, 1H), 2.14-2.09 (m,1H), 1.76-1.71 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 2) the Preparation of Compound 18-3

To a solution of compound 18-2 (3.63 g, 13.1 mmol) and compound 1-10(3.63 g, 13.1 mmol) in DCM (40.0 mL) was added TEA (2.73 mL, 19.65 mmol)dropwise at 0° C. At the end of the addition, the mixture was stirred atrt for 2.0 hrs. After the reaction was completed, the reaction wasquenched with water (50 mL), and the resulting mixture was extractedwith DCM (50 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the titlecompound (4.96 g), which was used for the next step without furtherpurification. The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 446.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.42-7.38 (m, 2H), 7.32-7.24 (m, 5H),7.18-7.15 (m, 2H), 5.17-5.08 (m, 4H), 4.37-4.34 (m, 1H), 3.30-3.22 (m,1H), 3.20-3.14 (m, 1H), 2.14-2.13, 2.11-2.09 (m, m, 1H), 1.72-1.71,1.69-1.67 (m, m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 3) the Preparation of Compound 18-4

A mixture of compound 18-3 (3.66 g, 8.2 mmol) and ammonium acetate (5.1g, 66 mmol) in toluene (30.0 mL) was refluxed at 110° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 50mL of water was added. The resulting mixture was extracted with EtOAc(80 mL×3), and the combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=4/1) to give the title compound(3.16 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 455.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.63-7.60 (m, 2H), 7.49-7.45 (m, 2H),7.31-7.24 (m, 6H), 5.25 (m, 2H), 5.10-5.05 (m, 1H), 3.45-3.38 (m, 1H),3.35-3.28 (m, 1H), 2.17-2.11 (m, 1H), 1.80-1.73 (m, 1H), 1.01-0.99 (m,3H), 0.86-0.84 (m, 3H).

Step 4) the Preparation of Compound 18-5

A mixture of compound 18-4 (3.14 g, 6.9 mmol), compound 1-14-2 (1.93 g,7.6 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.28 g, 0.34 mmol) and KOAc (1.7 g, 17.25mmol) in DME (30.0 mL) was stirred at 90° C. under N₂ for 2.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (200 mL) and filtered through a celite pad. The filtrate waswashed with water (50 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/2) to give the title compound (3.04 g,88%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 502.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.23-8.20 (m, 2H), 7.79-7.76 (m, 2H),7.32-7.24 (m, 5H), 7.23 (s, 1H), 5.25 (m, 2H), 5.10-5.05 (m, 1H),3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 2.17-2.11 (m, 1H), 1.80-1.73 (m,1H), 1.35, 1.32 (m, m, 12H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 5) the Preparation of Compound 18-6

To a mixture of compound 18-5 (3.86 g, 7.7 mmol), compound 1-8 (3.43 g,7.7 mmol), Pd(PPh₃)₄ (0.45 g, 0.38 mmol) and K₂CO₃ (2.1 g, 15.4 mmol)were added DME (32.0 mL) and pure water (8.0 mL) via syringe. Themixture was stirred at 90° C. under N₂ for 3.0 hrs. After the reactionwas completed, the mixture was concentrated in vacuo. The residue wasdissolved in EtOAc (150 mL), and then washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=2/1) to give the title compound as a pale yellow solid (3.74 g,70%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 694.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.71-7.66 (m, 4H), 7.39 (s, 1H),7.32-7.25 (m, 5H), 7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (d, d,1H), 5.25 (m, 2H), 5.10-5.05 (m, 1H), 3.45-3.38 (m, 1H), 3.35-3.28 (m,1H), 2.90-2.86 (m, 2H), 2.84-2.82 (m, 2H), 2.17-2.11 (m, 1H), 1.79-1.74(m, 1H), 1.73-1.42 (m, 8H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 6) the Preparation of Compound 18-8

To a solution of compound 18-7 (10.48 g, 35.5 mmol) in dry THF (250 mL),compound 1-19 (7.6 g, 35.5 mmol) and NaOH (1 M, 85.0 mmol) were added inturn. At the end of the addition, the mixture was stirred at rt for 1.0hr. After the reaction was completed, the mixture was extracted withEtOAc (100 mL×3). The combined organic layers were washed with NaOHaqueous solution (1M, 15 mL) and brine, dried over Na₂SO₄ andconcentrated in vacuo to give the title compound(18.1 g, 100%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 474.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.11-9.10 (m, 1H), 7.89-7.88 (m, 1H),7.54-7.49 (m, 2H), 7.32-7.24 (m, 5H), 6.39 (s, 2H), 5.14-5.13 (m, 2H),4.55-4.51 (m, 1H), 3.28-3.21 (m, 1H), 3.19-3.12 (m, 1H), 2.33-2.27 (m,1H), 1.96-1.90 (m, 1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 7) the Preparation of Compound 18-9

A solution of compound 18-8 (18.07 g, 38.1 mmol) and KOH (34.0 mL, 10%aq) in EtOH (200 mL) was stirred at 80° C. for 3.0 hrs. After thereaction was completed, the mixture was cooled to 0° C. and neutralizedto pH 7 by carefully adding concentrated HCl. The resulting precipitatewas collected by filtration and washed with EtOAc/hexane (v/v=5/1) togive the title compound 18-9 (13.38 g, 77.0%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 456.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02-8.01 (dd, 1H), 7.65, 7.62 (d, d,1H), 7.32-7.24 (m, 5H), 7.20-7.18 (d, d, 1H), 5.17-5.09 (m, 3H),3.28-3.21 (m, 1H), 3.18-3.12 (m, 1H), 2.43-2.38 (m, 1H), 2.01-1.95 (m,1H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 8) the Preparation of Compound 18-10

A mixture of compound 18-9 (0.2 g, 0.44 mmol), compound 1-14-2 (0.13 g,0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc (0.11 g, 1.12mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (60 mL) and filtered through a celite pad. The filtrate was washedwith water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a paleyellow solid (0.18 g, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 504.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.60-8.59 (dd, 1H), 7.78, 7.76 (d, d,1H), 7.62, 7.60 (d, d, 1H), 7.32-7.24 (m, 5H), 5.17-5.09 (m, 3H),3.28-3.21 (m, 1H), 3.18-3.12 (m, 1H), 2.43-2.38 (m, 1H), 2.01-1.95 (m,1H), 1.24, 1.20 (q, q, 12H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 9) the Preparation of Compound 18-11

To a mixture of compound 18-10 (0.50 g, 1.0 mmol), compound 18-6 (0.69g, 1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol)were added DME (6.0 mL) and H₂O (2.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 3.0 hrs. After the reaction wascompleted, the mixture was cooled to rt, diluted with EtOAc (50 mL). Theresulting mixture was washed with water (20 mL×3) and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/MeOH (v/v)=100/1) to give thetitle compound as a pale yellow solid (0.41 g, 45%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 461.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.97, 7.95 (d, d, 1H), 7.94-7.93 (m,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H),7.47-7.44 (m, 2H), 7.32-7.24 (m, 10H), 5.25 (m, 2H), 5.17-5.07 (m, 4H),3.45-3.38 (m, 1H), 3.35-3.28 (m, 1H), 3.27-3.21 (m, 1H), 3.18-3.12 (m,1H), 2.93-2.88 (m, 4H), 2.43-2.38 (m, 1H), 2.17-2.11 (m, 1H), 2.01-1.95(m, 1H), 1.80-1.73 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H),1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).

Step 10) the Preparation of Compound 18-12

To a solution of compound 18-11 (1.84 g, 2.0 mmol) in EtOAc (10.0 mL)was added a catalytic amount of Pd/C (0.2 g), then the mixture wasstirred at 40° C. under 10 atm of H₂ gas for 5.0 hrs. After the reactionwas completed, the mixture was filtered. The filtrate was concentratedin vacuo to give the title compound 18-12 (1.20 g, 90%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 653.4 [M+H]⁺.

Step 11) the Preparation of Compound 18-13

To a suspension of compound 18-12 (0.19 g, 0.29 mmol), compound 1-13-2(0.11 g, 0.65 mmol), EDCI (120 mg, 0.65 mmol) and HOAT (80 mg, 0.59mmol) in DCM (5.0 mL) was added DIPEA (0.49 mL, 2.97 mmol) dropwise at0° C. At the end of the addition, the mixture was stirred at rt for 3.0hrs. After the reaction was completed, the mixture was diluted with DCM(20 mL). The resulting mixture was washed with NH₄Cl aqueous solutionand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) togive the title compound as a white solid (0.18 g, 65%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 485.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.88, 7.86 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H),7.47-7.44 (m, 2H), 5.32-5.26 (m, 3H), 5.21-5.16 (m, 1H), 4.40-4.36 (m,1H), 4.28-4.24 (m, 1H), 3.63 (s, 6H), 3.57-3.50 (m, 1H), 3.46-3.39 (m,1H), 3.36-3.29 (m, 1H), 3.27-3.20 (m, 1H), 2.93-2.88 (m, 4H), 2.38-2.33(m, 1H), 2.28-2.22 (m, 1H), 2.20-2.08 (m, 1H), 2.03-1.91 (m, 2H),1.88-1.81 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.01-0.99 (m,6H), 0.97-0.95 (m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.84 (m, 6H).

Example 19

Synthetic Route:

Step 11) the Preparation of Compound 19-2

To a suspension of compound 18-12 (0.51 g, 0.78 mmol), compound 19-1(0.39 g, 1.64 mmol), EDCI (315 mg, 1.64 mmol) and HOAT (0.21 g, 1.56mmol) in DCM (7.0 mL) was added DIPEA (1.09 mL, 6.26 mmol) dropwise at0° C. At the end of the addition, the mixture was stirred at rt for 3.0hrs. After the reaction was completed, the mixture was diluted with DCM(20 mL). The resulting mixture was washed with NH₄Cl aqueous solutionand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=40/1) togive the title compound as a white solid (0.51 g, 60%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 546.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) ((ppm): 7.94 (m, 1H), 7.88, 7.86 (d, d, 1H),7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H), 7.47-7.44(m, 2H), 7.36-7.30 (m, 4H), 7.24-7.19 (m, 2H), 7.13-7.10 (m, 4H), 5.48,5.46 (d, d, 2H), 5.31-5.25 (m, 1H), 5.21-5.16 (m, 1H), 4.47-4.42 (m,1H), 4.35-4.31 (m, 1H), 3.57-3.50 (m, 1H), 3.46-3.39 (m, 1H), 3.36-3.29(m, 1H), 3.27-3.20 (m, 1H), 2.93-2.88 (m, 4H), 2.38-2.33 (m, 1H),2.28-2.21 (m, 1H), 2.20-2.10 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.93 (m,1H), 1.88-1.81 (m, 1H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.01-0.99(m, 6H), 0.97-0.95 (m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.84 (m, 6H).

Example 20

Synthetic Route:

Step 1) the Preparation of Compound 20-1

A mixture of compound 7-1 (2.29 g, 3.32 mmol), compound 1-14-2 (1.68 g,6.63 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.54 g, 0.66 mmol) and KOAc (0.98 g,9.96 mmol) in DME (15.0 mL) was stirred at 90° C. under N₂ for 3 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (100 mL) and filtered through a celite pad. The filtrate waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/2) to give the title compound as awhite solid (1.79 g, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 669.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94 (q, 1H), 7.84, 7.82 (d, d, 1H),7.78, 7.76 (dd, dd, 1H), 7.52-7.50 (d, d, 1H), 7.45, 7.42 (d, d, 1H),5.32, 5.29 (d, d, 1H), 5.21-5.15 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s,1H), 3.51-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.02-2.98 (m, 2H), 2.78-2.75(m, 2H), 2.50-2.42 (m, 1H), 2.37-2.27 (m, 1H), 2.11-1.98 (m, 2H),1.93-1.83 (m, 1H), 1.72-1.52 (m, 4H), 1.51-1.40 (m, 2H), 1.32, 1.29 (m,m, 12H), 1.28-1.19 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Step 2) the Preparation of Compound 20-2

To a mixture of compound 20-1 (2.30 g, 3.44 mmol), compound 20-1-2 (1.79g, 3.78 mmol), Pd(PPh₃)₄ (0.40 g, 0.34 mmol) and K₂CO₃ (1.19 g, 8.62mmol) were added DME (12.0 mL) and H₂O (4.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, diluted with EtOAc (100mL). The resulting mixture was was washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=25/1) togive the title compound as a pale yellow solid (1.98 g, 65%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 888.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.96 (m, 1H), 7.94-7.93 (q, 1H), 7.83,7.81 (d, d, 1H), 7.59-7.53 (m, 5H), 7.52, 7.50 (d, d, 1H), 7.46, 7.44(dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.17-5.11 (m, 1H), 4.31-4.22 (m,3H), 3.63 (s, 6H), 3.61-3.55 (m, 1H), 3.52-3.45 (m, 1H), 3.44-3.36 (m,1H), 3.34-3.27 (m, 1H), 2.93-2.88 (m, 4H), 2.41-2.32 (m, 1H), 2.20-1.49(m, 15H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m,6H).

Example 21

Synthetic Route:

Step 1) the Preparation of Compound 21-2

To a suspension of PPh₃MeBr (5.05 g, 14.2 mmol) in THF (50.0 mL) wasadded potassium tert-butanolate (14.9 mL, 14.9 mmol, 1.0 M in THF)dropwise at −20° C. At the end of the addition, the mixture was warmedto −5° C. and stirred for 30 mins, and then compound 21-1 (1.72 g, 7.07mmol) was added. At the end of the addition, the mixture was stirred atrt for 3.0 hrs. After the reaction was completed, the mixture wasquenched with ice water (50 mL), and THF was removed. The aqueous layerwas extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=5/1) to give the title compound (1.07 g, 62.9%) as paleyellow oil. The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 242.12 [M+H]⁺; and

¹H NMR (400 Mhz, DMSO-d₆) δ (ppm): 5.01 (d, 2H, J=10.8 Hz), 4.36 (t, 1H,J=11.2 Hz), 3.95 (s, 2H), 3.64 (s, 3H), 3.01 (q, 1H, J=14.6 Hz),2.57-2.50 (m, 1H), 1.38 (s, 9H).

Step 2) the Preparation of Compound 21-3

To a solution of diethylzinc (2.30 g, 18.60 mmol) in toluene (30.0 mL)was added chloroiodomethane (6.57 g, 37.24 mmol) dropwise at 0° C., andthe mixture was stirred at 0° C. for 45 mins. The solution of compound21-2 (1.5 g, 6.22 mmol) in toluene (15.0 mL) was then added. At the endof the addition, the mixture was stirred at 0° C. for 18 hrs. After thereaction was completed, the reaction was quenched with saturated NH₄Claqueous solution (20 mL) and the aqueous layer was extracted with EtOAc(25 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as whiteliquid (0.58 g, 36.5%) as white oil. The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 156.2 [M−Boc]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.47-4.33 (m, 1H), 3.71 (s, 3H),3.37-3.29 (m, 2H), 2.25-2.17 (m, 1H), 1.86-1.75 (m, 1H), 1.44, 1.40 (s,s, 9H), 0.62-0.50 (m, 4H).

Step 3) the Preparation of Compound 21-4

To a solution of compound 21-3 (0.69 g, 2.7 mmol) in EtOAc (6.0 mL) wasadded a solution of HCl in EtOAc (5.0 mL, 4 M) dropwise. At the end ofthe addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the mixture was concentrated in vacuo to givethe title compound (0.5 g, 96.5%) as colorless oil. The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 156.2 [M+H]⁺; and

¹H NMR (400 MHz, CD₃OD) δ (ppm): 4.66-4.62 (m, 1H), 4.45-4.44 (m, 1H),3.86 (s, 3H), 3.61-3.60 (m, 1H), 2.39-2.34 (m, 1H), 2.19-2.14 (m, 1H),1.49-1.46 (m, 1H), 1.19-1.16 (m, 1H), 0.88-0.87 (m, 1H), 0.81-0.79 (m,1H).

Step 4) the Preparation of Compound 21-5

A suspension of compound 21-4 (0.53 g, 2.77 mmol), compound 1-13-2 (0.73g, 4.16 mmol) and EDCI (1.06 g, 5.55 mmol) in DCM (10.0 mL) was stirredat 0° C., and then DIPEA (2.4 mL, 14.52 mmol) was added dropwise. At theend of the addition, the mixture was stirred at rt for 3.0 hrs. Afterthe reaction was completed, the mixture was diluted with DCM (20 mL),washed with NH₄Cl aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound(0.61 g, 70.2%) as white liquid. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 313.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.44-5.42 (br, 1H), 4.71-4.68 (m, 1H),4.29-4.20 (m, 1H), 3.73 (s, 3H), 3.72-3.69 (m, 1H), 3.67 (s, 3H),3.59-3.54 (m, 1H), 2.20-2.15 (m, 1H), 2.06-2.01 (m, 1H), 1.95-1.90 (m,1H), 1.05-0.93 (m, 6H), 0.66-0.61 (m, 4H).

Step 5) the Preparation of Compound 21-6

To a solution of compound 21-5 (0.20 g, 0.64 mmol) in THF (5.0 mL) wasadded lithium hydroxide monohydrate aqueous solution (0.13 g, 3.20 mmol,5.0 mL) at 0° C. At the end of the addition, the mixture was stirred at40° C. for 12 hrs. After the reaction was completed, the solvent THF wasremoved and 10 mL of water was added. The resulting mixture wasextracted with EtOAc (25 mL×3), and the aqueous layer was adjusted to pH1 with hydrochloric acid (10%), and then extracted with EtOAc (25 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound (0.16 g, 82.8%) as awhite solid. The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 299.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.06 (br, 1H), 5.76 (br, 1H), 4.73-4.69(m, 1H), 4.23-4.18 (m, 1H), 3.79 (d, 1H, J=9.7 Hz), 3.66 (s, 3H), 3.49(d, 1H, J=9.7 Hz), 2.26-2.18 (m, 1H), 2.07-1.93 (m, 2H), 1.00-0.94 (m,6H), 0.68-0.64 (m, 4H).

Step 6) the Preparation of Compound 21-7

A solution of compound 1-10 (0.31 g, 1.11 mmol), compound 21-6 (0.30 g,1.00 mmol) in MeCN (10.0 mL) was stirred at 0° C. under N₂, and thenDIPEA (0.21 mL, 1.27 mmol) was added dropwise. At the end of theaddition, the mixture was stirred at rt for 2.0 hrs. After the reactionwas completed, 20 mL of water was added and MeCN was removed. Theresulting mixture was dissolved in EtOAc (30 mL), washed with NH₄Claqueous solution and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/1) to give the title compound (0.33 g, 66.7%) as apale yellow solid. The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 495.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.82-7.78 (m, 2H), 7.67-7.64 (m, 2H),5.32, 5.29 (br, br, 1H), 5.31 (s, 2H), 4.72-4.70 (m, 1H), 4.35-4.30 (m,1H), 3.67 (s, 3H), 3.61-3.59 (m, 1H), 3.55-3.49 (m, 1H), 2.20-2.07 (m,2H), 1.83-1.76 (m, 1H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H),0.52-0.39 (m, 4H).

Step 7) the Preparation of Compound 21-8

To a solution of compound 21-7 (0.33 g 0.67 mmol) in xylene (10.0 mL)was added NH₄OAc (1.04 g, 13.43 mmol), and the mixture was stirred at120° C. for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt and 20 mL of water was added. The resulting mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/2) to give the title compound (0.19 g, 58.9%) as a yellow solid.The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 475.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.58 (s, 1H), 7.45-7.41 (m, 2H),7.29-7.26 (m, 2H), 5.46, 5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.41-4.37(m, 1H), 3.71-3.67 (m, 1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32(m, 1H), 2.23-2.11 (m, 1H), 2.05-1.97 (m, 1H), 0.97, 0.95 (m, m, 3H),0.91, 0.89 (m, m, 3H), 0.52-0.39 (m, 4H).

Step 8) the Preparation of Compound 21-9

To a mixture of compound 21-8 (0.19 g, 0.40 mmol), compound 1-14-2 (0.15g, 0.59 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (33 mg, 0.04 mmol) and KOAc (0.12 g,1.19 mmol) was added DMF (10.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was cooled to rt and 50 mL of water was added. The resultingmixture was extracted with EtOAc (40 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound (0.17 g, 80%) as a beigesolid. The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 523.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.64-7.57 (m, 4H), 7.21 (s, 1H), 5.46,5.44 (br, br, 1H), 4.93-4.89 (m, 1H), 4.42-4.37 (m, 1H), 3.71-3.67 (m,1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m,1H), 2.05-1.97 (m, 1H), 1.35 (m, 6H), 1.32 (m, 6H), 0.97, 0.95 (m, m,3H), 0.91, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H).

Step 9) the Preparation of Compound 21-10

To a mixture of compound 1-8 (3.43 g, 7.7 mmol), compound 21-9 (4.02 g,7.7 mmol), Pd(PPh₃)₄ (0.45 g, 0.38 mmol) and K₂CO₃ (2.1 g, 15.4 mmol)were added DME (32.0 mL) and water (8.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 3.0 hrs. After the reaction wascompleted, the mixture was cooled to rt and diluted with EtOAc (200 mL).The combined organic layer was washed with water (50 mL×3) and brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound (3.58 g, 65%) as a pale yellow solid. Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 715.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.60-7.57 (m, 3H), 7.48-7.45 (m, 2H),7.24, 7.22 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.32, 5.29 (d, d, 1H),4.93-4.89 (m, 1H), 4.41-4.37 (m, 1H), 3.72-3.66 (m, 1H), 3.63 (s, 3H),3.50-3.44 (m, 1H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.39-2.32 (m,1H), 2.23-2.11 (m, 1H), 2.05-1.97 (m, 1H), 1.74-1.42 (m, 8H), 0.97, 0.95(m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.55-0.42 (m, 4H).

Step 10) the Preparation of Compound 21-11

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 21-6 (3.12g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of the addition, the mixture was stirred at rt for 8.0 hrs. Afterthe reaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL) and washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/2) to give the title compound ascolorless slurry (0.69 g, 20%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 495.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.55-7.49 (m, 2H),6.39 (s, 2H), 5.56, 5.55 (d, d, 1H), 4.46-4.36 (m, 2H), 3.66 (s, 3H),3.39-3.33 (m, 1H), 3.31-3.25 (m, 1H), 2.53-2.46 (m, 1H), 2.22-2.10 (m,2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H), 0.49-0.36 (m, 4H).

Step 11) the Preparation of Compound 21-12

A solution of compound 21-11 (0.63 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.After the reaction was completed, the solvent THF was removed, and thenthe residue was dissolved in EtOAc (30 mL). The combined organic phasewere washed with water and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a white solid (0.52g, 85%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 477.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.70 (m, 3H), 5.32, 5.29 (d, d,1H), 5.08-5.04 (m, 1H), 4.30-4.25 (m, 1H), 3.63 (s, 3H), 3.45-3.39 (m,1H), 3.29-3.23 (m, 1H), 2.53-2.46 (m, 1H), 2.21-2.13 (m, 1H), 2.06-1.94(m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.47-0.34 (m,4H).

Step 12) the Preparation of Compound 21-13

A suspension of compound 21-12 (0.21 g, 0.44 mmol), compound 1-14-2(0.13 g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc(0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for3.0 hrs. After the reaction was completed, the mixture was cooled to rtand diluted with EtOAc (20 mL). The resulting mixture was washed withwater (10 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a pale yellow solid(0.19 g, 80%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 525.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13, 8.11 (d, d, 1H), 7.77 (m, 1H),7.47, 7.45 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.11-5.06 (m, 1H),4.30-4.25 (m, 1H), 3.63 (s, 3H), 3.45-3.39 (m, 1H), 3.29-3.23 (m, 1H),2.53-2.46 (m, 1H), 2.21-2.13 (m, 1H), 2.06-1.94 (m, 1H), 1.32, 1.29 (m,m, 12H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H), 0.47-0.34 (m,4H).

Step 13) the Preparation of Compound 21-14

A mixture of compound 21-10 (0.71 g, 1.0 mmol), compound 21-13 (0.52 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), washed with water (20 mL×3)and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/25) to give the title compound as a pale yellow solid (0.43 g,45%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 482.3 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.88-7.86 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 3H), 7.52-7.49 (m, 2H),7.47-7.44 (m, 2H), 5.32, 5.29 (d, d, 2H), 5.21-5.16 (m, 1H), 4.93-4.89(m, 1H), 4.42-4.37 (m, 1H), 4.30-4.25 (m, 1H), 3.72-3.66 (m, 1H), 3.63(s, 6H), 3.50-3.39 (m, 2H), 3.29-3.23 (m, 1H), 2.93-2.88 (m, 4H),2.54-2.46 (m, 1H), 2.39-2.32 (m, 1H), 2.23-2.11 (m, 2H), 2.06-1.94 (m,2H), 1.70-1.49 (m, 6H), 1.45-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90,0.89 (m, m, 6H), 0.55-0.34 (m, 8H).

Example 22

Synthetic Route:

Step 1) the Preparation of Compound 22-1

To a solution of compound 10-6 (3.91 g, 17.22 mmol) and compound 1-10(5.47 g, 19.81 mmol) in DCM (60.0 mL) was added DIPEA (3.4 mL, 20.67mmol) dropwise at 0° C. At the end of the addition, the mixture wasstirred at rt for 3 hrs. After the reaction was completed, the mixturewas quenched with water (80 mL), and the resulting mixture was extractedwith DCM (100 mL×3). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=5/1) to give the title compound as awhite solid (4.5 g, 61.73%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 424.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.73 (m, 2H), 7.64-7.62 (m, 2H),5.53-5.09 (m, 2H), 4.78-4.67 (m, 1H), 3.59-3.46 (m, 1H), 2.69-2.62 (m,1H), 2.43-2.40 (m, 1H), 1.42 (s, 9H), 1.00-0.96 (m, 1H), 0.76-0.69 (m,2H).

Step 2) the Preparation of Compound 22-2

A mixture of compound 22-1 (4.5 g, 10.64 mmol) and acetamide (16.4 g,212.73 mmol) in toluene (50.0 mL) was stirred at 110° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, and 50mL of water was added. The resulting mixture was extracted with EtOAc(100 mL×3), and the combined organic layers were dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=8/1) to give the title compound(2.14 g, 50%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 404.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.62-7.52 (br, 2H), 7.49-7.46 (d, 2H,J=12 Hz), 7.21 (s, 1H), 5.27-5.24 (d, 1H, J=10.0 Hz), 3.31-3.27 (m, 1H),1.71-1.67 (m, 2H), 1.52 (s, 9H), 0.89-0.86 (m, 1H), 0.69-0.64 (m, 2H).

Step 3) the Preparation of Compound 22-3

A mixture of compound 22-2 (2.1 g, 5.2 mmol), compound 1-14-2 (1.59 g,6.25 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.43 g, 0.52 mmol) and KOAc (1.54 g,15.63 mmol) in DMF (30.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (50 mL) and filtered through a celite pad. To the filtratewas added 150 mL of water, and the mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the titlecompound (2.27 g, 97%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 452.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.81-7.79 (d, 2H, J=8.04 Hz), 7.60 (br,2H), 7.26 (s, 1H), 5.28-5.26 (d, 1H, J=8.0 Hz), 3.53 (br, 1H), 3.30-3.27(br, 1H), 1.67-1.66 (m, 2H), 1.52 (s, 9H), 1.34 (s, 12H), 0.89-0.86 (m,1H), 0.69-0.64 (m, 2H).

Step 4) the Preparation of Compound 22-4

To a solution of compound 22-3 (5.46 g, 12.1 mmol) in EtOAc (40.0 mL)was added a solution of HCl in EtOAc (20 mL, 4 M) dropwise. At the endof the addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the reaction mixture was concentrated in vacuo,and EtOAc (50 mL) was added. The mixture was stirred and pulped, thenfiltered to give the title compound as a white solid (4.11 g, 80%),which was used for the next step without further purification. Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 352.5 [M+H]⁺.

Step 5) the Preparation of Compound 22-5

A suspension of compound 22-4 (1.10 g, 2.6 mmol), compound 1-13-2 (0.6g, 2.86 mmol) and EDCI (0.55 g, 2.86 mmol) in DCM (15.0 mL) was stirredat 0° C., then DIPEA (1.72 mL, 10.4 mmol) was added dropwise. At the endof the addition, the mixture was stirred at rt for 3.0 hrs. After thereaction was completed, the mixture was diluted with DCM (40 mL). Theresulting mixture was washed with NH₄Cl aqueous solution and brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound as a white solid (0.77 g, 58%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.64-7.57 (m, 4H), 7.29 (s, 1H), 5.32,5.29 (d, d, 1H), 4.89-4.85 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s, 3H),3.45-3.38 (m, 1H), 2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.00-1.94 (m,1H), 1.43-1.37 (m, 1H), 1.35, 1.32 (m, m, 12H), 0.97, 0.95 (m, m, 3H),0.94-0.89 (m, 4H), 0.50-0.46 (m, 1H).

Step 6) the Preparation of Compound 22-6

To a mixture of compound 22-5 (0.41 g, 0.81 mmol), compound 1-8 (0.36 g,0.81 mmol), Pd(PPh₃)₄ (47 mg, 0.04 mmol) and K₂CO₃ (0.29 g, 2.04 mmol)were added DME (8.0 mL) and pure water (2.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt and diluted with EtOAc (40mL). The resulting mixture was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (DCM/EtOH (v/v)=100/1) to give thetitle compound as a white solid (0.31 g, 55%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 701.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.62 (s, 1H), 7.60-7.57 (m, 2H),7.48-7.45 (m, 2H), 7.24-7.23, 7.22-7.21 (m, m, 1H), 7.03-7.02, 7.00 (dd,dd, 1H), 5.32, 5.29 (d, d, 1H), 4.89-4.85 (m, 1H), 4.09-4.04 (m, 1H),3.63 (s, 3H), 3.45-3.38 (m, 1H), 2.89-2.86 (m, 2H), 2.85-2.82 (m, 2H),2.46-2.39 (m, 1H), 2.22-2.09 (m, 1H), 2.00-1.94 (m, 1H), 1.74-1.36 (m,9H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H), 0.50-0.46 (m, 2H).

Step 7) the Preparation of Compound 22-7

A mixture of compound 22-6 (0.70 g, 1.0 mmol), compound 10-11 (0.51 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (40 mL), and washed with water andbrine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (MeOH/DCM(v/v)=1/30) to give the title compound as a pale yellow solid (0.42 g,45%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 468.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (q, 1H), 7.88, 7.86 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.62 (s, 1H), 7.60-7.57 (m, 2H), 7.52-7.49(m, 3H), 7.46, 7.44 (dd, dd, 1H), 5.32, 5.29 (d, d, 2H), 5.15-5.11 (m,1H), 4.89-4.85 (m, 1H), 4.35-4.31 (m, 1H), 4.09-4.04 (m, 1H), 3.63 (s,6H), 3.45-3.38 (m, 1H), 3.30-3.23 (m, 1H), 2.93-2.88 (m, 4H), 2.46-2.38(m, 2H), 2.22-2.09 (m, 1H), 2.07-1.94 (m, 3H), 1.70-1.35 (m, 10H), 0.97,0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H), 0.86-0.80 (m, 1H), 0.50-0.46 (m,2H), 0.41-0.38 (m, 1H).

Example 23

Synthetic Route:

Step 1) the Preparation of Compound 23-2

To a solution of (R)-1-phenylethylamine (1.3 mL, 10.1 mmol) in toluene(15.0 mL) was added anhydrous Na₂SO₄ (3.48 g, 24.5 mmol) at rt, followedby ethyl glyoxalate (1 mL, 10.1 mmol) dropwise, and the mixture wasstirred at rt for 1 hr and filtered. The filtrate was concentrated invacuo to give the title compound as yellow liquid (1.9 g, 91.8%), whichwas used for the next step without further purification.

Step 2) the Preparation of Compound 23-3

To a solution of compound 23-2 (2.0 g, 9.7 mmol) in DMF (15.0 mL) wasadded TFA (0.75 mL, 10.1 mmol). After 2 mins, to the mixture were addedfreshly prepared 1,3-cyclopentadiene (1.29 g, 19.5 mmol) and two dropsof water in turn. The reaction mixture was stirred for another 12 hrs,then the solvent DMF was removed and NaHCO₃ aqueous solution (20 mL,10%) was added. The mixture was adjusted to pH 8 with Na₂CO₃ andextracted with PE (25 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=10/1) to give the titlecompound as pale yellow liquid (2.38 g, 90%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.35-7.17 (m, 5H), 6.42 (br, 1H),6.28-6.26 (br, 1H), 4.34-4.30 (m, 2H), 3.82-3.78 (m, 2H), 3.04-3.02 (m,1H), 2.90 (br, 1H), 2.20 (br, 1H), 2.13 (m, 1H), 1.41 (d, 3H, J=6.6 Hz),0.95 (t, 3H, J=7.2 Hz).

Step 3) the Preparation of Compound 23-4

To a solution of compound 23-3 (2 g, 7.37 mmol) in ethanol (60.0 mL) wasadded Pd/C (0.20 g). The mixture was stirred at rt under 20 atm of H₂gas for 24 hrs. After the reaction was completed, the mixture wasfiltered. The filtrate was concentrated in vacuo to give the titlecompound as yellow liquid (1.2 g, 96.2%). The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 170.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.21-4.15 (m, 2H), 3.55 (br, 1H), 3.33(br, 1H), 2.63 (br, 1H), 2.32 (br, 1H), 1.64-1.60 (m, 2H), 1.53-1.47 (m,2H), 1.42-1.36 (m, 2H), 1.28 (t, 3H, J=7.1 Hz).

Step 4) the Preparation of Compound 23-5

To a solution of compound 23-4 (0.68 g, 4.02 mmol), compound 1-13-2(1.06 g, 6.03 mmol) and EDCI (1.54 g, 8.05 mmol) in DCM (25.0 mL) wasadded DIPEA (2.1 mL, 12.7 mmol) dropwise at 0° C., and the mixture wasstirred at rt overnight. After the reaction was completed, 30 mL ofwater was added to the mixture, and the resulting mixture was extractedwith CH₂Cl₂ (35 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the titlecompound as a white solid (0.74 g, 56.4%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 327.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 5.44 (br, 1H), 4.40 (br, 1H), 4.33-4.30(m, 1H), 4.19-4.14 (m, 2H), 4.02 (br, 1H), 3.66 (s, 3H), 2.74 (br, 1H),2.04 (br, 1H), 1.91-1.88 (m, 2H), 1.80-1.74 (m, 2H), 1.56-1.54 (m, 1H),1.43-1.38 (m, 1H), 1.26 (t, 3H, J=7.1 Hz), 1.07 (d, 3H, J=6.8 Hz), 0.97(d, 3H, J=6.8 Hz).

Step 5) the Preparation of Compound 23-6

To a solution of compound 23-5 (0.74 g, 2.27 mmol) in THF (25.0 mL) wasadded lithium hydroxide monohydrate aqueous solution (0.48 g, 11.35mmol, 10 mL) at 0° C., and the mixture was stirred at 40° C. for 12 hrs.After the reaction was completed, the solvent THF was removed and 20 mLof water was added to the mixture. The resulting mixture was washed withEtOAc (15 mL×3), and the aqueous phase was adjusted to pH 1 withhydrochloric acid (10%) and extracted with EtOAc (25 mL×3). The combinedorganic layers were washed by brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound as a white solid (0.55g, 81.3%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 299.2 [M+H]⁺; and

¹H NMR (400 MHz, CD₃OD) δ (ppm): 4.52 (br, 1H), 4.20 (d, 1H, J=7.8 Hz),3.93 (br, 1H), 3.63 (s, 3H), 2.73 (br, 1H), 2.01-1.98 (m, 4H), 1.85-1.75(m, 2H), 1.54-1.46 (m, 2H), 1.05 (d, 3H, J=6.8 Hz), 0.98 (d, 3H, J=6.8Hz).

Step 6) the Preparation of Compound 23-7

To a mixture of compound 1-10 (0.31 g, 1.11 mmol) and compound 23-6 (0.3g, 1.01 mmol) in DCM (10.0 mL) was added DIPEA (0.20 mL, 1.21 mmol)dropwise under N₂ at 0° C. At the end of the addition, the mixture wasstirred at rt for 3.0 hrs. After the reaction was completed, the residuewas diluted with water (40 mL). The resulting mixture was extracted withEtOAc (50 mL×3), and the combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=1/2) togive the title compound as a pale yellow solid (0.33 g, 66.7%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 495.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.75 (d, 2H, J=8.52 Hz), 7.68 (d, 2H,J=8.56 Hz), 5.45 (d, 1H, J=9.4 Hz), 5.24 (d, 1H, J=16.56 Hz), 4.59-4.55(m, 1H), 3.67 (s, 3H), 3.57 (m, 1H), 2.73-2.65 (m, 2H), 2.27-2.19 (m,1H), 2.04 (s, 1H), 1.84-1.77 (m, 2H), 1.49-1.46 (m, 1H), 1.27-1.24 (m,1H), 1.08-1.07 (br, 1H), 1.05-1.03 (m, 1H), 0.91-0.89 (m, 6H).

Step 7) the Preparation of Compound 23-8

To a solution of compound 23-7 (0.33 g, 0.67 mmol) in toluene (8.0 mL)was added NH₄OAc (1.04 g, 13.43 mmol), and the mixture was stirred at110° C. for 5.0 hrs. After the reaction was completed, the mixture wascooled to rt, 20 mL of water was added, and the resulting mixture wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=1/2) to give the title compound as a yellow solid (0.19 g, 58.9%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 476.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.35 (s, 1H), 7.64-7.62 (d, 2H, J=8.52Hz), 7.55-7.45 (d, 2H, J=1.84 Hz), 7.16 (s, 1H), 5.54-5.46 (br, 2H),4.57-4.53 (m, 1H), 3.70 (s, 3H), 3.58 (m, 1H), 2.69 (m, 1H), 2.54-2.48(m, 1H), 1.87-1.76 (m, 4H), 1.47-1.45 (m, 2H), 0.85-0.81 (m, 6H).

Step 8) the Preparation of Compound 23-9

To a mixture of compound 23-8 (0.19 g, 0.40 mmol), compound 1-14-2 (0.15g, 0.59 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (33 mg, 0.04 mmol) and KOAc (0.12 g,1.19 mmol) was added DMF (5.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. for 3.0 hrs. After the reaction was completed, themixture was cooled to rt, 20 mL of water was added, and the resultingmixture was extracted with EtOAc (20 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (0.17g, 80%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 523.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.48 (s, 1H), 7.81-7.75 (m, 4H),7.43-7.41 (d, 1H, J=8.0 Hz), 5.49-5.39 (m, 2H), 4.58-4.53 (m, 2H), 3.67(s, 3H), 3.57 (m, 1H), 2.65 (m, 1H), 2.54-2.47 (m, 1H), 2.10-2.04 (m,2H), 1.83-1.79 (m, 1H), 1.49-1.46 (m, 2H), 1.38 (s, 12H), 0.85-0.81 (m,6H).

Step 9) the Preparation of Compound 23-10

To a mixture of compound 23-9 (0.42 g, 0.81 mmol), compound 1-8 (0.36 g,0.81 mmol), Pd(PPh₃)₄ (47 mg, 0.04 mmol) and K₂CO₃ (0.29 g, 2.04 mmol)were added DME (8.0 mL) and pure water (2.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt and diluted with EtOAc (40mL), and the resulting mixture was washed with water and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/EtOH (v/v)=100/1) togive the title compound as a white solid (0.35 g, 60%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 715.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.61-7.57 (m, 2H), 7.48-7.45 (m, 2H),7.24-7.23, 7.22-7.21 (dd, dd, 1H), 7.02, 7.00 (dd, dd, 1H), 5.56, 5.55(d, d, 1H), 5.06-5.02 (m, 1H), 4.80-4.75 (m, 1H), 4.21-4.17 (m, 1H),3.66 (s, 3H), 2.90-2.86 (m, 2H), 2.85-2.82 (m, 2H), 2.55-2.50 (m, 1H),2.26-2.14 (m, 1H), 2.08-2.00 (m, 1H), 1.83-1.78 (m, 1H), 1.74-1.37 (m,13H), 1.02, 1.00 (m, m, 3H), 0.94, 0.92 (m, m, 3H).

Step 10) the Preparation of Compound 23-11

To a suspension of compound 1-19 (1.5 g, 7.0 mmol), compound 23-6 (3.12g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15.0 mL) and THF(10.0 mL) was added DIPEA (5.8 mL, 35 mmol) at 0° C. under N₂. At theend of addition, the mixture was stirred at rt for 8.0 hrs. After thereaction was completed, the solvent was removed. The residue wasdissolved in EtOAc (100 mL) and washed with water and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/2) to give the title compound ascolorless slurry (0.69 g, 20%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 495.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89-7.88 (m, 1H), 7.56, 7.53 (dd, dd,1H), 7.51, 7.49 (m, m, 1H), 6.39 (s, 2H), 5.56, 5.55 (d, d, 1H),4.71-4.67 (m, 1H), 4.48-4.44 (m, 1H), 4.17-4.13 (m, 1H), 3.66 (s, 3H),2.52-2.48 (m, 1H), 2.22-2.10 (m, 1H), 1.87-1.79 (m, 1H), 1.72-1.60 (m,2H), 1.59-1.50 (m, 1H), 1.42-1.28 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H).

Step 11) the Preparation of Compound 23-12

A solution of compound 23-11 (0.63 g, 1.28 mmol) in THF (10.0 mL) wasadded lithium hydroxide aqueous solution (0.27 g, 6.0 mL) at 0° C. Atthe end of the addition, the mixture was stirred at rt for 5.0 hrs.After the reaction was completed, the solvent THF was removed, and thenthe residue was dissolved in EtOAc (30 mL), washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the titlecompound as a white solid (0.52 g, 85%). The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 477.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.77-7.74 (m, 2H), 7.72, 7.70 (m, 1H),5.32, 5.29 (d, d, 1H), 4.96-4.92 (m, 1H), 4.66-4.62 (m, 1H), 4.34-4.29(m, 1H), 3.63 (s, 3H), 2.53-2.49 (m, 1H), 2.07-1.94 (m, 2H), 1.86-1.77(m, 1H), 1.73-1.59 (m, 3H), 1.22-1.15 (m, 1H), 0.97, 0.95 (m, m, 3H),0.90, 0.89 (m, m, 3H).

Step 12) the Preparation of Compound 23-13

A suspension of compound 23-12 (0.21 g, 0.44 mmol), compound 1-14-2(0.13 g, 0.51 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (40 mg, 0.05 mmol) and KOAc(0.11 g, 1.12 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for3.0 hrs. After the reaction was completed, the mixture was cooled to rt,diluted with EtOAc (20 mL) and filtered through a celite pad. Thefiltrate was washed with water (10 mL×3) and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/3) to give the title compound asa pale yellow solid (0.19 g, 80%).

The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 525.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.14, 8.12 (d, d, 1H), 7.75-7.74 (m,1H), 7.47, 7.45 (d, d, 1H), 5.32-5.29 (d, d, 1H), 4.99-4.95 (m, 1H),4.66-4.62 (m, 1H), 4.34-4.29 (m, 1H), 3.63 (s, 3H), 2.53-2.49 (m, 1H),2.07-1.94 (m, 2H), 1.86-1.77 (m, 1H), 1.73-1.59 (m, 3H), 1.32, 1.29 (m,m, 12H), 1.22-1.15 (m, 1H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Step 13) the Preparation of Compound 23-14

A mixture of compound 23-10 (0.71 g, 1.0 mmol), compound 21-13 (0.52 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (MeOH/DCM (v/v)=1/25) to give the title compoundas a pale yellow solid (0.43 g, 45%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 482.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.89, 7.87 (d, d, 1H), 7.86, 7.84 (dd,dd, 1H), 7.61-7.56 (m, 4H), 7.54-7.49 (m, 3H), 6.72-6.71 (dd, 1H), 6.08,6.05 (d, d, 1H), 5.56, 5.55 (d, d, 1H), 5.06-5.02 (m, 1H), 4.82-4.75 (m,2H), 4.66-4.62 (m, 2H), 4.21-4.17 (m, 1H), 4.14-4.10 (m, 1H), 3.66, 3.65(s, s, 6H), 3.06-3.03 (m, 2H), 2.92-2.88 (m, 2H), 2.55-2.49 (m, 2H),2.26-2.14 (m, 1H), 2.11-1.98 (m, 3H), 1.86-1.77 (m, 2H), 1.73-1.49 (m,14H), 1.47-1.35 (m, 2H), 1.22-1.15 (m, 1H), 1.02, 1.00 (m, m, 6H), 0.93,0.91 (m, m, 6H).

Example 24

Synthetic Route:

Step 1) the Preparation of Compound 24-2

To a suspension of compound 24-1 (3.48 g, 18.6 mmol), compound 1-13-2(3.26 g, 18.6 mmol) and EDCI (7.1 g, 37 mmol) in DCM (50.0 mL) was addedDIPEA (12.3 mL, 74.4 mmol) at 0° C. At the end of the addition, themixture was stirred at rt for 3.0 hrs. After the reaction was completed,the mixture was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=3/1) to give the title compound as paleyellow oil (2.5 g, 39.1%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 Hz, CDCl₃) δ (ppm): 5.32, 5.29 (d, d, 1H), 4.95-4.91 (m,1H), 4.33-4.29 (In, 1H), 4.01-4.00 (In, 4H), 3.80-3.78 (m, 1H), 3.72 (s,3H), 3.63 (s, 3H), 3.55-3.50 (m, 1H), 2.76-2.70 (m, 1H), 2.35-2.29 (m,1H), 2.18-2.06 (In, 1H), 0.97, 0.95 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Step 2) the Preparation of Compound 24-3

To a solution of compound 24-2 (0.9 g, 2.6 mmol) in THF (5.0 mL) wasadded a solution of LiOH (0.12 g, 5.0 mmol) in water (5.0 mL). At theend of the addition, the mixture was stirred at 40° C. for 12 hrs. Afterthe reaction was completed, THF was removed and water (20 mL) was added.The mixture was adjusted to pH 2 with diluted hydrochloric acid (1 M),and then extracted with EtOAc (25 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo to give the title compound as a white solid (0.85 g, 99%), whichwas used for the next step without further purification. The compoundwas characterized by the following spectroscopic data:

¹H NMR (400 Hz, CD₃Cl) δ (ppm): 9.80 (s, 1H), 4.54 (d, 1H, J=7.25 Hz),4.28 (m, 1H), 4.06 (m, 4H), 3.76 (m, 2H), 3.50 (s, 3H), 2.71 (m, 2H),2.65 (m, 1H), 0.87 (m, 3H), 0.81 (m, 3H).

Step 3) the Preparation of Compound 24-4

To a mixture of compound 1-10 (1.65 g, 5.9 mmol) and compound 24-3 (1.78g, 5.4 mmol) in MeCN (30.0 mL) was added DIPEA (1.1 mL, 6.7 mmol)dropwise at 0° C. At the end of the addition, the mixture was stirred atrt for 3.0 hrs. After the reaction was completed, the mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=3/1) to give the title compound as a paleyellow solid (2.76 g, 97.3%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.30 (s, 1H), 7.95 (d, 2H, J=8.27 Hz),7.71 (d, 2H, J=8.25 Hz), 5.72-5.34 (m, 2H), 4.52 (d, 1H), 4.29 (m, 1H),4.19 (m, 4H), 3.77 (m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H),0.91 (m, 3H), 0.89 (m, 3H).

Step 4) the Preparation of Compound 24-5

A suspension of compound 24-4 (3.0 g, 5.7 mmol) and NH₄OAc (4.4 g, 57.1mmol) in toluene (20.0 mL) was stirred at 110° C. overnight. After thereaction was completed, the mixture was cooled to rt and diluted withEtOAc (40 mL). The resulting mixture was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the titlecompound as a yellow solid (2.6 g, 89.9%). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.30 (s, 1H), 7.95 (d, 2H, J=8.27 Hz),7.71 (d, 2H, J=8.25 Hz), 4.52 (d, 1H), 4.29 (m, 1H), 4.19 (m, 4H), 3.77(m, 2H), 3.69 (s, 3H), 2.71 (m, 1H), 2.65 (m, 2H), 0.91 (m, 3H), 0.89(m, 3H).

Step 5) the Preparation of Compound 24-6

A suspension of compound 24-5 (1.68 g, 3.32 mmol), compound 1-14-2 (1.68g, 6.63 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.54 g, 0.66 mmol) and KOAc (0.98 g,9.96 mmol) in DME (20.0 mL) was stirred at 90° C. under N₂ for 4.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (100 mL) and filtered through a celite pad. The filtrate waswashed with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/DCM (v/v)=1/2) to give the title compound as a whitesolid (1.45 g, 79.2%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 555.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.64-7.58 (m, 4H), 7.22 (s, 1H),5.40-5.36 (m, 1H), 5.32, 5.29 (brs, brs, 1H), 4.42-4.38 (m, 1H),3.98-3.96 (m, 2H), 3.94-3.92 (m, 2H), 3.71-3.69 (m, 1H), 3.67-3.66 (m,1H), 3.63 (s, 3H), 2.83-2.78 (m, 1H), 2.45-2.39 (m, 1H), 2.23-2.11 (m,1H), 1.35 (br, 6H), 1.32 (br, 6H), 0.97-0.95 (m, 3H), 0.91-0.89 (m, 3H).

Step 6) the Preparation of Compound 24-7

A mixture of compound 7-1 (0.69 g, 1.0 mmol), compound 24-6 (0.55 g, 1.0mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) in themixed solvent of DME/H₂O (v/v=3/1, 8.0 mL) was stirred at 90° C. underN₂ for 3.0 hrs. After the reaction was completed, the mixture was cooledto rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) andbrine. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (MeOH/DCM (v/v)=1/30) to give the title compound as apale yellow solid (0.44 g, 45%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 485.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (q, 1H), 7.83, 7.81 (d, d,1H), 7.71, 7.69 (dd, dd, 1H), 7.60-7.57 (m, 2H), 7.52-7.49 (m, 3H),7.46, 7.44 (dd, dd, 1H), 7.35 (s, 1H), 6.08, 6.06 (d, d, 2H), 5.40-5.36(m, 1H), 5.21-5.16 (m, 1H), 4.35-4.25 (m, 2H), 3.99-3.92 (m, 4H),3.71-3.69 (m, 1H), 3.67-3.66 (m, 1H), 3.65 (s, 6H), 3.60-3.54 (m, 1H),3.23-3.17 (m, 1H), 2.93-2.88 (m, 4H), 2.83-2.77 (m, 1H), 2.45-2.36 (m,3H), 2.28-2.16 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 1H), 1.70-1.49(m, 6H), 1.45-1.35 (m, 2H), 1.02, 1.00 (m, m, 6H), 0.93, 0.91 (m, m,6H).

Example 25

Synthetic Route:

Step 1) the Preparation of Compound 25-1

To a suspension of compound 1-3 (7.29 g, 45.0 mmol) and triethylsilane(20.98 g, 180 mmol) was added TFA (30.0 mL) dropwise at 0° C. At the endof the addition, the mixture was stirred at 40° C. for 24 hrs. After thereaction was completed, the mixture was concentrated in vacuo. Theresidue was dissolved in EtOAc (150 mL). The resulting mixture waswashed with Na₂CO₃ aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/DCM (v/v)=15/1) to give the title compound(5.2 g, 78%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 149.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.03-6.96 (m, 2H), 6.68-6.66 (m, 1H),3.86 (s, 3H), 2.99-2.81 (m, 4H), 2.24-2.05 (m, 2H).

Step 2) the Preparation of Compound 25-2

To a solution of compound 25-1 (10.34 g, 69.8 mmol) and NIS (17.2 g,76.8 mmol) in MeCN (200 mL) was added TFA (0.52 mL, 6.98 mmol) dropwiseat 0° C. At the end of the addition, the mixture was stirred at rtovernight. After the reaction was completed, the mixture was quenchedwith saturated NaHCO₃ aqueous solution (100 mL). The aqueous layer wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE) to givethe title compound (16.44 g, 86%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 275.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.42, 7.40 (t, t, 1H), 6.41-6.40,6.39-6.38 (m, m, 1H), 3.87 (s, 3H), 2.96-2.76 (m, 4H), 2.37-2.18 (m,2H).

Step 3) the Preparation of Compound 25-3

To a solution of compound 25-2 (16.35 g, 59.7 mmol) in DCM (150 mL) wasadded boron tribromide (74.7 g, 298.8 mmol) dropwise at −78° C. At theend of the addition, the reaction mixture was stirred at rt for 1.0 hr.After the reaction was completed, the mixture was quenched with icewater (200 mL) and the organic phase was separated. The aqueous layerwas extracted with EtOAc (100 mL×3). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=40/1) to give the title compound (14.28 g, 92%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 261.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.32, 7.30 (t, t, 1H), 6.32, 6.30 (t,t, 1H), 4.81 (br, 1H), 2.90-2.74 (m, 4H), 2.36-2.18 (m, 2H).

Step 4) the Preparation of Compound 25-4

A mixture of compound 25-3 (0.42 g, 1.62 mmol), compound 1-14-2 (0.42 g,1.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (67 mg, 0.08 mmol) and KOAc (0.40 g, 4.05mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (50 mL) and filtered through a celite pad. The filtrate was washedwith water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound (0.30 g,70%) as a pale yellow solid. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 261.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94, 7.92 (t, t, 1H), 6.71, 6.69 (t,t, 1H), 4.81 (br, 1H), 2.97-2.92 (m, 2H), 2.87-2.70 (m, 2H), 2.29-2.10(m, 2H), 1.32, 1.29 (m, m, 12H).

Step 5) the Preparation of Compound 25-5

A mixture of compound 25-4 (0.88 g, 3.40 mmol), compound 7-1 (2.35 g,3.40 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)in the mixed solvent of DME/H₂O (15 mL, v/v=4/1) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (80 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=20/1) to give the title compound(1.03 g, 45%) as a pale yellow solid. The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 675.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.62, 7.59 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.38, 7.35 (dd, dd,1H), 6.97, 6.94 (m, m, 1H), 6.65, 6.63 (t, t, 1H), 6.07, 6.05 (d, d,1H), 5.21-5.16 (m, 1H), 4.81 (brs, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H),3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.04-2.87 (m, 6H), 2.75-2.70 (m,2H), 2.45-2.36 (m, 1H), 2.32-2.15 (m, 2H), 2.13-2.01 (m, 2H), 1.94-1.72(m, 2H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H),0.93, 0.91 (m, m, 3H).

Step 6) the Preparation of Compound 25-6

To a solution of compound 25-5 (6.74 g, 10.0 mmol) in DCM (20.0 mL) wasadded pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL,40.0 mmol) was added. At the end of the addition, the mixture wasstirred at rt for 1.0 hr. After the reaction was completed, the mixturewas quenched with ice water (50 mL). The aqueous layer was extractedwith DCM (30 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound (6.45 g, 80%) as white oil. The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.83, 7.81 (d, d,1H), 7.62, 7.59 (dd, dd, 1H), 7.52, 7.50 (d, d, 1H), 7.38, 7.35 (dd, dd,1H), 7.15-7.14, 7.13-7.12 (t, t, 1H), 6.89, 6.86 (t, t, 1H), 6.08, 6.05(d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H),3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.06-2.87 (m, 6H), 2.75-2.70 (m,2H), 2.45-2.19 (m, 3H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.50(m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.94, 0.91 (m, m,3H).

Step 7) the Preparation of Compound 25-7

A mixture of compound 25-6 (1.31 g, 1.62 mmol 1), compound 1-14-2 (0.42g, 1.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (67 mg, 0.08 mmol) and KOAc (0.40 g,4.05 mmol) in DMF (8.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (80 mL) and filtered through a celite pad. The filtrate waswashed with water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/3) to give the title compound (0.89 g,70%) as a pale yellow solid. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 785.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.92, 7.90 (t, t,1H), 7.83, 7.81 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.44, 7.42 (dd, dd,1H), 7.38-7.33 (m, 2H), 6.08, 6.06 (d, d, 1H), 5.21-5.16 (m, 1H),4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H),3.13-3.09 (m, 2H), 2.92-2.87 (m, 4H), 2.78-2.73 (m, 2H), 2.45-2.36 (m,1H), 2.24-2.01 (m, 4H), 1.94-1.72 (m, 2H), 1.70-1.49 (m, 6H), 1.45-1.35(m, 2H), 1.32-1.29 (m, m, 12H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m,3H).

Step 8) the Preparation of Compound 25-8

A mixture of compound 25-7 (2.67 g, 3.40 mmol), compound 7-8 (1.57 g,3.74 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)in the mixed solvent of DME/H₂O (15.0 mL, v/v=4/1) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (100 mL), and washed with water (50mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1) to give the title compound(1.45 g, 45%) as a pale yellow solid. The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 476.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94-7.93 (m, 1H), 7.85 (s, 1H), 7.83,7.81 (d, d, 1H), 7.52, 7.50 (d, d, 1H), 7.43-7.40 (m, 2H), 7.38, 7.35(d, d, 1H), 7.33, 7.31 (m, m, 1H), 5.32-5.28 (m, 3H), 5.21-5.16 (m, 1H),4.41-4.36 (m, 1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m,1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 2.92-2.76 (m,8H), 2.44-2.37 (m, 1H), 2.31-1.73 (m, 11H), 1.70-1.49 (m, 6H), 1.46-1.35(m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 26

Synthetic Route:

Step 1) the Preparation of Compound 26-2

A mixture of compound 26-1 (0.44 g, 1.62 mmol), compound 1-14-2 (0.42 g,1.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (67.0 mg, 0.08 mmol) and KOAc (0.40 g,4.05 mmol) in DMF (5.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt, dilutedwith EtOAc (50 mL) and filtered through a celite pad. The filtrate waswashed with water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=15/1) to give the title compound (0.31 g,70%) as a pale yellow solid. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 271.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.53-8.50 (m, 1H), 8.45-8.43 (m, 1H),7.83, 7.81 (m, m, 1H), 7.62-7.58 (m, 1H), 7.52-7.48 (m, 1H), 7.06, 7.04(br, br, 1H), 6.17 (br, 1H), 1.57 (m, 6H), 1.54 (m, 6H).

Step 2) the Preparation of Compound 26-3

A mixture of compound 26-2 (0.92 g, 3.4 mmol), compound 7-1 (2.35 g, 3.4mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol) inthe mixed solvent of DME/H₂O (15.0 mL, v/v=4/1) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (60 mL), and then washed with water(20.0 mL×3) and brine. The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the titlecompound (1.05 g, 45%) as a pale yellow solid. The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 685.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.25-8.24, 8.23-8.22 (m, m, 1H),7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.65, 7.62 (dd, dd, 1H), 7.52,7.50 (d, d, 1H), 7.48-7.44 (m, 2H), 7.41-7.39 (m, m, 1H), 7.33, 7.31(brs, brs, 1H), 7.22-7.17 (m, 1H), 7.04, 7.02 (m, m, 1H), 6.17 (brs,1H), 6.08, 6.05 (d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.25 (m, 1H), 3.65(s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H),2.98-2.94 (m, 2H), 2.45-2.36 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m,2H), 1.70-1.49 (m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H).

Step 3) the Preparation of Compound 26-4

To a solution of compound 26-3 (6.84 g, 10.0 mmol) in DCM (40.0 mL) wasadded pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL,40.0 mmol) was added. At the end of the addition, the mixture wasstirred at rt for 1.0 hr. After the reaction was completed, the mixturewas quenched with ice water (50 mL). The aqueous layer was extractedwith DCM (30 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) togive the title compound (6.94 g, 85%) as white oil. The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃): δ (ppm): 8.38-8.37, 8.36-8.35 (m, m, 1H),7.94-7.93 (m, 1H), 7.83, 7.81 (d, d, 1H), 7.66, 7.64 (dd, dd, 1H), 7.63,7.60 (m, m, 1H), 7.52-7.46 (m, 2H), 7.41-7.39 (m, m, 1H), 7.34, 7.31 (m,m, 1H), 7.26, 7.24, 7.22 (m, m, m, 1H), 7.17-7.15 (m, m, 1H), 6.07, 6.05(d, d, 1H), 5.21-5.16 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H),3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m,2H), 2.45-2.36 (m, 1H), 2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.49(m, 6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m,3H).

Step 4) the Preparation of Compound 26-5

A mixture of compound 26-4 (1.32 g, 1.62 mmol), compound 1-14-2 (0.42 g,1.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (67 mg, 0.08 mmol) and KOAc (0.40 g, 4.05mmol) in DMF (10.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs. Afterthe reaction was completed, the mixture was cooled to rt, diluted withEtOAc (60 mL) and filtered through a celite pad. The filtrate was washedwith water (20 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=1/3) to give the title compound (0.9 g,70%) as a pale yellow solid. The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 795.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.81, 8.79 (m, m, 1H), 8.17, 8.14 (m,m, 1H), 7.94-7.93 (q, 1H), 7.90, 7.87 (brs, brs, 1H), 7.83, 7.81 (d, d,1H), 7.79-7.75 (m, 2H), 7.60-7.56 (m, 1H), 7.52, 7.50 (d, d, 1H), 7.48,7.46 (dd, dd, 1H), 7.22-7.18 (m, 1H), 6.08, 6.05 (d, d, 1H), 5.21-5.16(m, 1H), 4.30-4.25 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H), 3.24-3.16(m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m, 2H), 2.45-2.36 (m, 1H),2.15-2.01 (m, 2H), 1.94-1.72 (m, 2H), 1.69-1.52 (m, 18H), 1.46-1.35 (m,2H), 1.02, 1.00 (m, m, 3H), 0.93, 0.91 (m, m, 3H).

Step 5) the Preparation of Compound 26-6

A mixture of compound 26-5 (2.70 g, 3.4 mmol), compound 7-8 (1.57 g,3.74 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)in the mixed solvent of DME/H₂O (15 mL, v/v=4/1) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (100 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1) to give the title compound(1.31 g, 40%) as a pale yellow solid. The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 481.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.02-8.01, 8.00-7.99 (m, m, 1H),7.94-7.93 (q, 1H), 7.88, 7.86 (m, m, 1H), 7.83, 7.81 (d, d, 1H), 7.74(s, 1H), 7.72, 7.70 (dd, dd, 1H), 7.63, 7.60 (m, m, 1H), 7.54-7.50 (m,2H), 7.48, 7.46 (dd, dd, 1H), 7.43-7.38 (m, 1H), 7.10-7.06 (m, 1H),5.36-5.31 (m, 1.5H), 5.29 (d, 0.5H), 5.21-5.16 (m, 1H), 4.41-4.36 (m,1H), 4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s,6H), 3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94(m, 2H), 2.44-2.37 (m, 1H), 2.30-1.73 (m, 9H), 1.69-1.49 (m, 6H),1.46-1.35 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 27

Synthetic Route:

Step 1) the Preparation of Compound 27-2

A solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) in anhydrousDMF (6.0 mL) was slowly added dropwise in the dark to a solution ofcompound 27-1 (0.72 g, 6.0 mmol) in anhydrous DMF (6.0 mL) at −15° C. Atthe end of the addition, the mixture was stirred at room temperature for1.0 hr and then at 60° C. for another 5.0 hrs. After the reaction wascompleted, the mixture was poured into 50 mL of ice water and 60.0 mL ofethyl ether. The organic layer was separated, washed several times withwater to neutral pH, and dried with anhydrous Na₂SO₄. The solvent wasevaporated to give an oily liquid (1.07 g, 65%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 275.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.02 (d, 1H), 7.53, 7.51 (s, s, 1H),7.34, 7.32 (d, d, 1H).

Step 2) the Preparation of Compound 27-3

A mixture of compound 27-2 (0.25 g, 0.91 mmol), compound 1-14-2 (0.53 g,2.09 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (71 mg, 0.09 mmol) and KOAc (0.27 g, 2.73mmol) in DMF (10.0 mL) was stirred at 90° C. under N₂ for 3.0 hrs. Aftercooling to room temperature, the mixture was diluted with EtOAc (60 mL)and filtered through a celite pad. The filtration was washed with water(30 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=5/2) to give the title compound (0.27 g, 80%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 372.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.53 (d, 1H), 8.53, 8.51 (d, d, 1H),7.94, 7.92 (d, d, 1H), 1.56, 1.54 (m, m, 12H), 1.32, 1.29 (m, m, 12H).

Step 3) the Preparation of Compound 27-4

To a mixture of compound 27-3 (0.27 g, 0.72 mmol), compound 25-7 (0.30g, 0.72 mmol), Pd(PPh₃)₄ (83 mg, 0.07 mmol) and K₂CO₃ (0.30 g, 2.12mmol) were added DME (4.0 mL) and water (1.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 10 mL ofwater, and the resulting mixture was extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/1) to give the title compound(0.23 g, 60%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 538.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.37 (d, 1H), 7.66 (s, 1H), 7.54, 7.52(d, d, 1H), 7.26, 7.24 (s, s, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d,1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s,3H), 2.30-1.92 (m, 5H), 1.56, 1.53 (m, m, 12H), 0.97-0.89 (m, 6H).

Step 4) the Preparation of Compound 27-5

To a mixture of compound 27-4 (0.54 g, 1 mmol), compound 7-1 (0.69 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol)were added DME (4.0 mL) and water (1.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 4.0 hrs. After the reaction wascompleted, the mixture was cooled to rt, followed by adding 10 mL ofwater, and the resulting mixture was extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=50/1) to give the title compound(0.48 g, 50%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 476.7 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.08 (dd, 1H), 7.94-7.93 (q, 1H),7.83-7.79 (m, 2H), 7.63 (s, 1H), 7.60, 7.57 (d, d, 1H), 7.52, 7.50 (d,d, 1H), 7.45, 7.43 (d, d, 1H), 7.38, 7.36 (dd, dd, 1H), 5.38-5.34 (m,1H), 5.32, 5.29 (d, d, 2H), 5.25-5.16 (m, 1H), 4.41-4.36 (m, 1H),4.30-4.25 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 6H),3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.02-2.99 (m, 2H), 2.98-2.94 (m,2H), 2.44-2.37 (m, 1H), 2.30-1.73 (m, 9H), 1.67-1.50 (m, 6H), 1.46-1.35(m, 2H), 0.97-0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 28

Synthetic Route:

Step 1) the Preparation of Compound 28-2

To a solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) and compound28-1 (2.54 g, 10 mmol) in CCl₄ (20.0 mL) was added benzoyl peroxide(0.24 g, 1.0 mmol) dropwise at 0° C. At the end of the addition, themixture was stirred at room temperature for 15 mins and then refluxedfor another 7.0 hrs. After the reaction was completed, the solvent wasremoved. The residue was dissolved in EtOAc (100 mL), and then washedwith water (50 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound (4.0 g), which was usedfor the next step without further purification. The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 335.8 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.70 (t, 1H), 4.73 (d, 2H).

Step 2) the Preparation of Compound 28-3

NaH (60%, 3.13 g, 78 mmol) was added to DMF (100 mL) followed bydropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end ofthe addition, the mixture was heated to 100° C. for 40 mins, and thencooled to room temperature. Compound 28-2 (11.81 g, 35.60 mmol) wasadded. The mixture was stirred for 30 mins at room temperature, and thenheated to 75° C. for another 1.0 hr. After the reaction was completed,the reaction was quenched with aqueous saturated NH₄Cl solution (50 mL),and then EtOAc (150 mL) was added to the mixture. The combined organiclayer was washed with water and brine, dried over anhydrous Na2SO4 andconcentrated in vacuo to give the title compound (14.0 g), which wasused for the next step. The compound was characterized by the followingspectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.93 (m, 1H), 4.18-4.13 (q, 4H),3.84-3.81 (m, 1H), 3.35, 3.33 (dd, dd, 2H), 1.23-1.19 (m, 6H).

Step 3) the Preparation of Compound 28-4

To a solution of compound 28-3 (14.0 g) in DMSO (100 mL) was added NaCl(4.10 g, 70 mmol) and water (0.64 g, 35.6 mmol) dropwise at rt. At theend of the addition, the mixture was stirred at 100° C. for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt anddiluted with 200 mL of EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound (9.0 g). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.88 (t, 1H), 4.11-4.06 (q, 2H), 3.05,3.03, 3.01 (m, m, m, 2H), 2.69-2.65 (m, 2H), 1.24-1.20 (m, 3H).

Step 4) the Preparation of Compound 28-5

To a solution of compound 28-4 (3.42 g, 10 mmol) in MeOH (20.0 mL) wasadded NaOH aqueous solution (800 mg, 20 mL) at 0° C., and the mixturewas stirred at rt for 3.0 hrs and adjusted to pH 5 with dilutedhydrochloric acid (1 M). The solvent MeOH was removed in vacuo, and theaqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M)and extracted with EtOAc (50 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo to give the titlecompound as a white solid (2.82 g, 90%). The compound was characterizedby the following spectroscopic data:

MS (ESI, pos.ion) m/z: 315.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.94 (brs, 1H), 6.93 (t, 1H), 3.05,3.03, 3.01 (m, m, m, 2H), 2.79, 2.77, 2.75 (d, d, d, 2H).

Step 5) the Preparation of Compound 28-6

To a solution of compound 28-5 (3.14 g, 10 mmol) in dry DCM (40.0 mL)and DMF (0.05 mL) was added oxalyl chloride (0.93 mL, 11 mmol) dropwiseat −10° C. At the end of the addition, the mixture was stirred at rt for1.0 hr. After the reaction was completed, the mixture was used for thenext step without further purification.

To a suspension of aluminium chloride (1.73 g, 13 mmol) in DCM (30.0 mL)was added the above solution dropwise at −15° C. At the end of addition,the mixture was stirred at −15° C. for 2.0 hrs. After the reaction wascompleted, the mixture was poured into ice water (100 mL) and theorganic phase was separated. The aqueous layer was extracted with DCM(30 mL×3). The combined organic layers were washed with water andsaturated Na₂CO₃ aqueous solution, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (PE/EtOAc (v/v)=10/1) to give the title compound as apale yellow solid (2.37 g, 80%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 296.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.96-2.93 (m, 2H), 2.81-2.78 (m, 2H).

Step 6) the Preparation of Compound 28-7

To a solution of compound 28-6 (2.96 g, 10 mmol), 1,4-dibromobutane(1.31 mL, 11 mmol) and TEBAC (0.46 g, 2.0 mmol) in DMSO (30.0 mL) wasadded sodium hydroxide aqueous solution (1.6 g, 40 mmol, 1.6 mL)dropwise at −5° C. At the end of the addition, the mixture was stirredat 60° C. for 8.0 hrs. After the reaction was completed, the mixture waspoured into ice water (100 mL) and filtered. The filter cake wasdissolved in EtOAc (50 mL). The solution was washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound (2.63 g, 75%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 351.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.65-2.63 (m, 2H), 1.94-1.64 (m, 6H),1.25-1.15 (m, 2H).

Step 7) the Preparation of Compound 28-8

To a suspension of compound 28-7 (3.5 g, 10 mmol), NH₄F (1.11 g, 30mmol) and triethylsilane (4.79 mL, 30 mmol) was added TFA (9.0 mL, 120mmol) dropwise at −5.0° C. At the end of the addition, the mixture wasstirred at 50° C. for 15 hrs. After the reaction was completed, themixture was concentrated in vacuo. The residue was dissolved in EtOAc(100 mL). The resulting mixture was washed with Na₂CO₃ aqueous solutionand brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound (2.87 g, 85%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 337.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.81-2.79 (m, 4H), 1.77-1.46 (m, 6H),1.34-1.24 (m, 2H).

Step 8) the Preparation of Compound 28-9

A mixture of compound 28-8 (0.34 g, 1.0 mmol), compound 1-15 (0.50 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=4/1, 5.0 mL) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1) to give the title compound(0.41 g, 65%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 626.6 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67-7.64 (m, 2H), 7.59 (s, 1H),7.51-7.48 (m, 2H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m, 1H), 4.41-4.36(m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s, 3H), 2.84-2.81(m, 2H), 2.75-2.72 (m, 2H), 2.30-1.92 (m, 5H), 1.75-1.54 (m, 4H),1.53-1.43 (m, 2H), 1.31-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89(m, m, 3H).

Step 9) the Preparation of Compound 28-10

A mixture of compound 28-9 (0.63 g, 1.0 mmol), compound 1-22 (0.50 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=4/1, 5.0 mL) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=30/1) to give the title compound(0.41 g, 45%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 459.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.24-8.23 (m, 1H), 7.77, 7.74 (d, d,1H), 7.66-7.62 (m, 2H), 7.59 (s, 1H), 7.50-7.45 (m, 3H), 5.32, 5.29 (d,d, 2H), 5.23-5.16 (m, 2H), 4.41-4.37 (m, 1H), 4.30-4.25 (m, 1H),3.85-3.78 (m, 1H), 3.68-3.66 (m, 1H), 3.63 (s, 6H), 3.60-3.54 (m, 1H),3.24-3.16 (m, 1H), 2.82-2.75 (m, 4H), 2.44-2.37 (m, 1H), 2.30-1.39 (m,15H), 1.29-1.18 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 29

Synthetic Route:

Step 1) the Preparation of Compound 29-2

To a solution of n-bromosuccinimide (NBS) (2.16 g, 12 mmol) and compound29-1 (2.51 g, 10 mmol) in CCl₄ (20.0 mL) was added benzoyl peroxide(0.24 g, 1.0 mmol) dropwise at 0° C. At the end of the addition, themixture was stirred at room temperature for 15 mins and then refluxedfor another 7.0 hrs. After the reaction was completed, the solvent wasremoved. The residue was dissolved in EtOAc (100 mL), and then washedwith water (50 mL×3) and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound (4.0 g), which was usedfor the next step without further purification. The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 330.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.18-8.17 (m, 1H), 7.79 (m, 1H),4.66-4.65 (m, 2H).

Step 2) the Preparation of Compound 29-3

NaH (60%, 3.13 g, 78 mmol) was added to DMF (100 mL) followed bydropwise addition of diethyl malonate (12.54 g, 78 mmol). At the end ofthe addition, the mixture was heated to 100° C. for 40 mins and thencooled to room temperature. Compound 29-2 (11.74 g, 35.60 mmol) wasadded. The mixture was stirred for 30 mins at room temperature, and thenheated to 75° C. for 1.0 hr. After the reaction was completed, themixture was quenched with aqueous saturated NH₄Cl solution (50 mL), andthen EtOAc (150 mL) was added to the mixture. The combined organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo to give the title compound (13.0 g), which was used for the nextstep. The compound was characterized by the following spectroscopicdata:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.14 (m, 1H), 7.75 (m, 1H), 4.18-4.13(q, 4H), 3.83-3.80 (m, 1H), 3.55-3.54, 3.53-3.52 (m, m, 2H), 1.23-1.19(t, 6H).

Step 3) the Preparation of Compound 29-4

To a solution of compound 29-3 (13.0 g) in DMSO (100 mL) were added NaCl(4.10 g, 70 mmol) and water (0.64 g, 35.6 mmol) dropwise at rt. At theend of the addition, the mixture was stirred at 100° C. for 3.0 hrs.After the reaction was completed, the mixture was cooled to rt anddiluted with 200 mL of EtOAc. The combined organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound (8.5 g). The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.08-8.07 (m, 1H), 7.75 (m, 1H),4.08-4.03 (q, 2H), 2.98-2.97, 2.96, 2.94 (m, m, m, 2H), 2.75, 2.74, 2.72(d, d, d, 2H), 1.22-1.19 (t, 3H).

Step 4) the Preparation of Compound 29-5

To a solution of compound 29-4 (3.37 g, 10 mmol) in MeOH (20.0 mL) wasadded NaOH aqueous solution (800 mg, 20 mL) at 0° C., and the mixturewas stirred at rt for 3.0 hrs and adjusted to pH 5 with dilutedhydrochloric acid (1 M). The solvent MeOH was removed in vacuo, and theaqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M)and extracted with EtOAc (50 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated in vacuo to give the title compoundas a white solid (2.78 g, 90%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 309.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.32 (brs, 1H), 8.08-8.07 (m, 1H),7.78 (m, 1H), 3.02-3.01, 3.00-2.99, 2.98-2.97 (m, m, m, 2H), 2.88, 2.86,2.84 (d, d, d, 2H).

Step 5) the Preparation of Compound 29-6

To a solution of compound 29-5 (3.09 g, 10 mmol) in dry DCM (40.0 mL)and DMF (0.05 mL) was added oxalyl chloride (0.93 mL, 11 mmol) dropwiseat −10° C. At the end of the addition, the mixture was stirred at rt for1.0 hr. After the reaction was completed, the mixture was used for thenext step without further purification.

To a suspension of aluminium chloride (1.73 g, 13 mmol) in DCM (30.0 mL)was added the above solution (3.27 g, 10 mmol) dropwise at −15° C. Atthe end of the addition, the mixture was stirred at −15° C. for 2.0 hrs.After the reaction was completed, the mixture was poured into ice-water(100 mL) and the organic phase was separated. The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith water and saturated Na₂CO₃ aqueous solution, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=10/1) to give the title compoundas a pale yellow solid (2.33 g, 80%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 292.5 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.38 (s, 1H), 3.22-3.20 (m, 2H),2.80-2.78 (m, 2H).

Step 6) the Preparation of Compound 29-7

To a solution of compound 29-6 (2.91 g, 10 mmol), 1,4-dibromobutane(1.31 mL, 11 mmol) and TEBAC (0.46 g, 2.0 mmol) in DMSO (30.0 mL) wasadded sodium hydroxide aqueous solution (1.6 g, 40 mmol, 1.6 mL)dropwise at −5° C. At the end of the addition, the mixture was stirredat 60° C. for 8.0 hrs. After the reaction was completed, the mixture waspoured into ice water (100 mL) and filtered. The filter cake wasdissolved in EtOAc (50 mL). The solution was washed with brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound (2.59 g, 75%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 346.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.38 (s, 1H), 3.07-3.06 (q, 2H),2.03-1.91 (m, 2H), 1.82-1.62 (m, 4H), 1.34-1.24 (m, 2H).

Step 7) the Preparation of Compound 29-8

To a suspension of compound 29-7 (3.45 g, 10 mmol), NH₄F (1.11 g, 30mmol) and triethylsilane (4.79 mL, 30 mmol) was added TFA (9.0 mL, 120mmol) dropwise at −5.0° C. At the end of the addition, the mixture wasstirred at 50° C. for 15 hrs. After the reaction was completed, themixture was concentrated in vacuo. The residue was dissolved in EtOAc(100 mL). The resulting mixture was washed with Na₂CO₃ aqueous solutionand brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound (2.81 g, 85%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 332.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.08 (dd, 1H), 3.23-3.20 (m, 2H),3.04-3.01 (m, 2H), 1.77-1.45 (m, 8H).

Step 8) the Preparation of Compound 29-9

A mixture of compound 29-8 (0.33 g, 1.0 mmol), compound 1-15 (0.50 g,1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) inthe mixed solvent of DME/H₂O (v/v=4/1, 5.0 mL) was stirred at 90° C.under N₂ for 4.0 hrs. After the reaction was completed, the mixture wascooled to rt, diluted with EtOAc (50 mL), and washed with water (20mL×3) and brine. The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1) to give the title compound(0.40 g, 65%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 621.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.58 (dd, 1H), 7.92-7.89 (m, 2H),7.75-7.72 (m, 2H), 7.59 (s, 1H), 5.32, 5.29 (d, d, 1H), 5.23-5.19 (m,1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63 (s,3H), 3.25-3.22 (m, 2H), 2.82-2.79 (m, 2H), 2.30-1.92 (m, 5H), 1.74-1.53(m, 6H), 1.52-1.42 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Step 9) the Preparation of Compound 29-10

A mixture of compound 29-9 (0.62 g, 1.0 mmol), compound 5-8 (0.53 g, 1.0mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol) in themixed solvent of DME/H₂O (v/v=4/1, 5.0 mL) was stirred at 90° C. underN₂ for 4.0 hrs. After the reaction was completed, the mixture was cooledto rt, diluted with EtOAc (50 mL), and washed with water (20 mL×3) andbrine. The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=30/1) to give the title compound (0.43 g,45%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 475.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.58 (dd, 1H), 8.27 (brs, 2H),7.91-7.88 (m, 2H), 7.82 (q, 1H), 7.78, 7.76 (d, d, 1H), 7.75-7.72 (m,2H), 7.59 (s, 1H), 7.53, 7.51 (d, d, 1H), 5.32, 5.29 (d, d, 2H),5.23-5.19 (m, 1H), 5.08-5.04 (m, 1H), 4.41-4.36 (m, 1H), 4.31-4.26 (m,1H), 3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 6H), 3.62-3.57 (m,1H), 3.26-3.18 (m, 1H), 3.06-3.03 (m, 2H), 2.85-2.82 (m, 2H), 2.38-1.39(m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 30

Synthetic Route:

Step 1) the Preparation of Compound 30-2

To a solution of compound 1-10-2 (23.0 g, 107 mmol) and compound HATU(48.82 g, 128.4 mmol) in THF (250 mL) was added DIPEA (19.5 mL, 118mmol) at 0° C. After stirring at 0° C. for 0.5 hr, to the solution wasadded compound 30-1 (22.25 g, 119 mmol) portionwise, and then thereaction mixture was stirred at rt for 4.0 hrs. After the reaction wascompleted, the reaction was quenched with water (100 mL). The solventTHF was removed, and the resulting mixture was extracted with EtOAc (200mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in glacial acetic acid(100 mL). The solution was stirred at 40° C. overnight, and HOAc wasremoved. The resulting mixture was dissolved in EtOAc (400 mL), washedwith Na₂CO₃ aq (150 mL×3), dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound (31.74 g, 81%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 367.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.68 (s, 1H), 7.42-7.40 (m, 1H),7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m,1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H).

Step 2) the Preparation of Compound 30-3

To a solution of compound 30-2 (10.0 g, 27.39 mmol) in EtOAc (50.0 mL)was added a solution of HCl in EtOAc (60.0 mL, 4 M) dropwise at 0° C.,and the mixture was stirred at rt. After the reaction was completed, themixture was filtered, and the filter cake was washed with EtOAc to givethe title compound as a pale yellow solid (8.0 g, 86.49%). The compoundwas characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 267.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.01 (s, 1H), 7.76-7.70 (m, 2H),5.27-5.25 (m, 1H), 3.31-3.30 (m, 2H), 2.77-2.74 (m, 1H), 2.54-2.52 (m,1H), 2.40-2.37 (m, 1H), 2.30-2.10 (m, 1H).

Step 3) the Preparation of Compound 30-4

To a solution of compound 30-3 (6.0 g, 18.8 mmol), compound 1-13-2 (4.9g, 28.2 mmol) and EDCI (5.4 g, 28.2 mmol) in DCM (100 mL) was addedDIPEA (18.6 mL, 112.8 mmol) dropwise at 0° C., and the mixture wasstirred at rt. After the reaction was completed, 100 mL of water wasadded to the mixture, and the resulting mixture was extracted with DCM(150 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated in vacuo, and the residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=1/2) to give the title compound asa solid (6.74 g, 85%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 423.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.59-7.51 (m, 1H), 7.34-7.21 (m, 2H),5.42-5.38 (m, 2H), 4.34-4.30 (m, 1H), 3.87-3.76 (m, 1H), 3.70 (s, 3H),3.66-3.62 (m, 1H), 3.04-2.98 (m, 1H), 2.25-2.20 (m, 1H), 2.20-2.13 (m,2H), 1.96-1.94 (m, 1H), 0.88-0.84 (m, 6H).

Step 4) the Preparation of Compound 30-5

To a mixture of compound 30-4 (3.0 g, 7.1 mmol), compound 1-14-2 (2.72g, 10.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.65 g, 0.8 mmol) and KOAc (2.09 g,21.3 mmol) was added DMF (30.0 mL) via syringe under N₂, and the mixturewas stirred at 90° C. After the reaction was completed, the mixture wascooled to rt, followed by adding 60 mL of water, and the resultingmixture was extracted with EtOAc (50 mL×3). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/2) to give the title compound as a beige solid (2.1 g,62.9%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 471.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.87-7.80 (m, 1H), 7.71-7.66 (m, 2H),5.47-5.42 (m, 2H), 4.34-4.30 (m, 1H), 3.86-3.84 (m, 1H), 3.70 (s, 3H),3.64-3.62 (m, 1H), 3.04-2.98 (m, 1H), 2.25-2.20 (m, 1H), 2.20-2.13 (m,2H), 1.96-1.94 (m, 1H), 1.35 (s, 12H), 0.88-0.84 (m, 6H).

Step 5) the Preparation of Compound 30-6

A mixture of compound 25-7 (0.88 g, 3.40 mmol), compound 29-8 (1.12 g,3.40 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)in the mixed solvent of DME/H₂O (15 mL, v/v=4/1) was stirred at 90° C.under N₂ for 4.0 hrs. After cooling to room temperature, the mixture wasdiluted with EtOAc (80 mL). The resulting mixture was washed with water(20 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=20/1) to give the title compound (0.59 g, 45%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 385.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44-8.43 (dd, 1H), 7.23, 7.21 (t, t,1H), 6.59, 6.57 (t, t, 1H), 4.81 (brs, 1H), 3.23-3.20 (m, 2H), 3.07-2.90(m, 2H), 2.86-2.82 (m, 2H), 2.81-2.76 (m, 2H), 2.32-2.13 (m, 2H),1.71-1.42 (m, 8H).

Step 6) the Preparation of Compound 30-7

To a solution of compound 30-6 (3.84 g, 10.0 mmol) in DCM (20.0 mL) wasadded pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (6.73 mL,40.0 mmol) was added. At the end of the addition, the mixture wasstirred at rt for 1.0 hr. After the reaction was completed, the mixturewas quenched with ice-water (50 mL). The aqueous layer was extractedwith DCM (30 mL×3). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=10/1) togive the title compound (4.13 g, 80%) as white oil. The compound wascharacterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44-8.43 (dd, 1H), 7.14, 7.12 (t, t,1H), 7.10, 7.08 (t, t, 1H), 3.23-3.20 (m, 2H), 3.09-2.92 (m, 2H),2.86-2.82 (m, 2H), 2.78-2.73 (m, 2H), 2.41-2.22 (m, 2H), 1.74-1.42 (m,8H).

Step 7) the Preparation of Compound 30-8

To a mixture of compound 30-7 (1.76 g, 3.40 mmol), compound 7-8 (1.43 g,3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 4.0 hrs. After the reaction wascompleted, the mixture was cooled to rt, 100 mL of EtOAc was added, andthe resulting mixture was washed with water (50 mL×3) and brine, driedover anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (DCM/MeOH (v/v)=100/1) togive the title compound (1.01 g, 45%). The compound was characterized bythe following spectroscopic data:

MS (ESI, pos.ion) m/z: 661.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.43 (s, 1H), 7.85 (s, 1H), 7.59, 7.57(t, t, 1H), 7.30, 7.28 (t, t, 1H), 5.32-5.28 (m, 2H), 4.41-4.36 (m, 1H),3.85-3.78 (m, 1H), 3.68-3.64 (m, 1H), 3.63 (s, 3H), 3.23-3.20 (m, 2H),2.93-2.88 (m, 2H), 2.86-2.83 (m, 2H), 2.79-2.75 (m, 2H), 2.35-1.92 (m,7H), 1.74-1.40 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Step 8) the Preparation of Compound 30-9

To a mixture of compound 30-8 (2.25 g, 3.40 mmol), compound 30-5 (1.60g, 3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 100 mLof EtOAc, and the resulting mixture was washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1) to give the title compound as a pale yellow solid (1.41 g,45%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 463.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.57 (s, 1H), 7.85 (s, 1H), 7.76, 7.73(d, d, 1H), 7.62 (dd, 1H), 7.58, 7.56 (t, t, 1H), 7.53, 7.51 (d, d, 1H),7.30, 7.28 (t, t, 1H), 5.32-5.28 (m, 3H), 5.25-5.20 (m, 1H), 4.41-4.35(m, 2H), 3.85-3.77 (m, 2H), 3.69-3.65 (m, 2H), 3.63 (s, 6H), 2.94-2.86(m, 6H), 2.79-2.75 (m, 2H), 2.37-1.88 (m, 12H), 1.71-1.50 (m, 6H),1.49-1.39 (m, 2H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89 (m, m, 6H).

Example 31

Synthetic Route:

Step 1) the Preparation of Compound 31-1

To a mixture of compound 26-2 (0.92 g, 3.40 mmol), compound 29-8 (1.12g, 3.40 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 80 mL ofEtOAc, and the resulting mixture was washed with water (20 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=20/1) to give the title compound as a pale yellow solid (0.67 g,50%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 395.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66-8.65 (dd, 1H), 8.35, 8.34 (m, m,1H), 7.64-7.59 (m, 1H), 7.54, 7.52 (brs, brs, 1H), 7.41-7.37 (m, 1H),7.30-7.27 (m, 1H), 7.12, 7.10 (brs, brs, 1H), 6.17 (brs, 1H), 3.31-3.28(m, 2H), 2.86-2.83 (m, 2H), 1.73-1.42 (m, 8H).

Step 2) the Preparation of Compound 31-2

To a solute ion of compound 31-1 (3.94 g, 10.0 mmol) in DCM (20.0 mL)was added pyridine (4.8 mL, 60.0 mmol) dropwise at 0° C. After themixture was stirred for 10 mins, trifluoromethanesulfonic anhydride(6.73 mL, 40.0 mmol) was added. At the end of the addition, the mixturewas stirred at rt for 1.0 hr. After the reaction was completed, themixture was quenched with ice water (50 mL). The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=10/1) to give the title compound as white oil (4.20 g, 80%). Thecompound was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.66-8.65 (dd, 1H), 8.49, 8.47 (m, m,1H), 7.97, 7.95 (brs, brs, 1H), 7.79-7.74 (m, 1H), 7.46-7.41 (m, 1H),7.36, 7.34 (brs, brs, 1H), 7.32-7.29 (m, 1H), 3.31-3.28 (m, 2H),2.86-2.83 (m, 2H), 1.74-1.42 (m, 8H).

Step 3) the Preparation of Compound 31-3

To a mixture of compound 31-2 (1.79 g, 3.40 mmol), compound 7-8 (1.43 g,3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22 mmol)were added DME (12.0 mL) and water (3.0 mL) via syringe, and the mixturewas stirred at 90° C. under N₂ for 4.0 hrs. After the reaction wascompleted, the mixture was cooled to rt, followed by adding 100 mL ofEtOAc, and the resulting mixture was washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=100/1) to give the title compound (1.03 g, 45%).

The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 671.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.65 (s, 1H), 8.07-8.04 (m, 1H),7.88-7.85 (m, 1H), 7.78, 7.76 (brs, brs, 1H), 7.74 (s, 1H), 7.59-7.48(m, 3H), 5.36-5.29 (m, 2H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H),3.68-3.65 (m, 1H), 3.63 (s, 3H), 3.31-3.28 (m, 2H), 2.86-2.83 (m, 2H),2.30-1.92 (m, 5H), 1.74-1.42 (m, 8H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89(m, m, 3H).

Step 4) the Preparation of Compound 31-4

To a mixture of compound 31-3 (2.28 g, 3.40 mmol), compound 30-5 (1.60g, 3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 100 mLof EtOAc, and the resulting mixture was washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1) to give the title compound as a pale yellow solid (1.43 g,45%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 468 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.52 (s, 1H), 8.07-8.04 (m, 1H),7.88-7.85 (m, 1H), 7.82-7.81, 7.80-7.79 (brs, brs, 1H), 7.76-7.73 (m,2H), 7.62-7.61 (dd, 1H), 7.59-7.58, 7.57-7.56 (m, m, 1H), 7.55-7.48 (m,3H), 5.36-5.29 (m, 3H), 5.25-5.20 (m, 1H), 4.41-4.35 (m, 2H), 3.85-3.77(m, 2H), 3.69-3.65 (m, 2H), 3.63 (s, 3H), 3.00-2.97 (m, 2H), 2.89-2.86(m, 2H), 2.37-1.87 (m, 10H), 1.74-1.39 (m, 8H), 0.97, 0.95 (m, m, 6H),0.90, 0.89 (m, m, 6H).

Example 32

Synthetic Route:

Step 1) the Preparation of Compound 32-1

To a mixture of compound 28-8 (1.14 g, 3.40 mmol), compound 27-4 (1.83g, 3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 100 mLof EtOAc, and the resulting mixture was washed with water (50 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1) to give the title compound(1.02 g, 45%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 667.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.65 (d, 1H), 7.77, 7.75 (d, d, 1H),7.63 (s, 1H), 7.60, 7.58 (s, s, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d,d, 1H), 4.41-4.36 (m, 1H), 3.85-3.78 (m, 1H), 3.68-3.65 (m, 1H), 3.63(s, 3H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 2.30-1.92 (m, 5H),1.75-1.43 (m, 6H), 1.32-1.21 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89(m, m, 3H).

Step 2) the Preparation of Compound 32-2

To a mixture of compound 32-1 (2.27 g, 3.40 mmol), compound 30-5 (1.60g, 3.4 mmol), Pd(PPh₃)₄ (0.20 g, 0.17 mmol) and K₂CO₃ (1.41 g, 10.22mmol) were added DME (12.0 mL) and water (3.0 mL) via syringe, and themixture was stirred at 90° C. under N₂ for 4.0 hrs. After the reactionwas completed, the mixture was cooled to rt, followed by adding 100 mLof EtOAc, and the resulting mixture was washed with water (50 mL×3) andbrine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (DCM/MeOH(v/v)=50/1) to give the title compound as a pale yellow solid (1.27 g,40%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 466 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.68 (d, 1H), 7.81-7.77 (m, 2H),7.67-7.66 (q, 1H), 7.63 (s, 1H), 7.52, 7.50 (s, s, 1H), 7.18, 7.16 (d,d, 1H), 5.38-5.34 (m, 1H), 5.32, 5.29 (d, d, 1H), 5.25-5.20 (m, 1H),4.41-4.35 (m, 2H), 3.85-3.77 (m, 2H), 3.69-3.66 (m, 2H), 3.63 (s, 6H),3.06-3.03 (m, 2H), 2.94-2.91 (m, 2H), 2.37-1.87 (m, 10H), 1.73-1.52 (m,4H), 1.50-1.39 (m, 2H), 1.28-1.18 (m, 2H), 0.97, 0.95 (m, m, 3H), 0.91,0.89 (m, m, 6H).

Example 33

Synthetic Route:

Step 1) the Preparation of Compound 33-2

The mixture of compound 33-1 (25 g, 125.6 mmol), NBS (24.5 g, 138.2mmol) and p-TSA (3.4 g, 20.9 mmol) was stirred at 100° C. for 2.0 hrsunder N₂. After the reaction was completed, the mixture was cooled tort, and 200 mL of DCM was added. The organic layer were washed withwater (50 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=5/1) to give the title compound (25 g, 71%). Thecompound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 279.9 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.95 (d, 1H, J=1.12 Hz), 8.14-8.11 (m,1H), 7.68-7.66 (m, 1H), 4.41 (s, 2H).

Step 2) the Preparation of Compound 33-3

To a solution of compound 33-2 (5.0 g, 17.9 mmol) and compound 1-19-2(5.36 g, 19.7 mmol) in MeCN (100 mL) was added DIPEA (3.3 mL, 19.7 mmol)dropwise at 0° C. At the end of the addition, the mixture was stirred atrt for 3.0 hrs. After the reaction was completed, the mixture wasquenched with ice water (50 mL), and the resulting mixture was extractedwith EtOAc (60 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=3/1) to give the titlecompound (8.0 g, 96%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 470.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.88 (s, 1H), 8.04 (d, 1H, J=3.88 Hz),7.65 (d, 1H, J=4.16 Hz), 5.61-5.59 (m, 1H), 5.48 (d, 1H, J=8.32 Hz),5.23 (d, 1H, J=8.3 Hz), 4.67 (t, 1H, J=5.72 Hz), 4.31 (t, 1H, J=7.52Hz), 3.86-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.66 (s, 3H), 2.34-2.15 (m,4H), 1.01 (t, 3H), 0.94-0.93 (m, 3H), 0.88-0.85 (m, 1H).

Step 3) the Preparation of Compound 33-4

A mixture of compound 33-3 (2.0 g, 4.25 mmol) and ammonium acetate (4.9g, 83 mmol) in xylene (50.0 mL) was refluxed at 130° C. for 5.0 hrs.After the reaction was completed, the mixture was cooled to rt, andquenched with 50 mL of water. The resulting mixture was extracted withEtOAc (50 mL×3), and the combined organic layers were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the titlecompound (1.39 g, 73%). The compound was characterized by the followingspectroscopic data:

MS (ESI, pos.ion) m/z: 450.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.70 (s, 1H), 7.93 (d, 1H, J=6.92 Hz),7.45 (d, 1H, J=8.28 Hz), 5.41 (d, 1H, J=4.6 Hz), 5.24-5.22 (m, 1H), 4.32(m, 1H), 3.85-3.83 (m, 1H), 3.67 (s, 3H), 3.63-3.62 (m, 3H), 3.05-3.03(m, 1H), 2.31-1.93 (m, 4H), 1.04-1.03 (m, 1H), 0.88 (s, 3H), 0.86 (s,3H).

Step 4) the Preparation of Compound 33-6

To a solution of formic acid (3.7 mL) was added triethylamine (5.4 mL)at 0° C., followed by compound 33-5 (1.85 g, 12 mmol) and2,2-dimethyl-1,3-dioxane-4,6-dione (1.73 g, 12 mmol). At the end of theaddition, the mixture was stirred at 100° C. for 2.0 hrs. After thereaction was completed, 20 mL of ice water was added to the mixture, andthe resulting mixture was adjusted to pH 1 with hydrochloric acid (2 M)and extracted with EtOAc (25 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EtOAc (v/v)=3/1) togive the title compound as a white solid (2.02 g, 85%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 199.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.60 (brs, 1H), 7.13-7.09 (m, 1H),6.82-6.81, 6.79-6.77 (m, m, 1H), 6.76-6.71 (m, 1H), 3.79 (d, 3H),2.90-2.85 (m, 2H), 2.62, 2.60, 2.58 (d, d, d, 2H).

Step 5) the Preparation of Compound 33-7

A mixture of compound 33-6 (4.42 g, 22.3 mmol) and PPA (50.87 g, 24.8mL) was stirred at 80° C. for 4.0 hrs. After the reaction was completed,250 mL of ice water was added to the mixture, and the resulting mixturewas extracted with EtOAc (100 mL×5). The combined organic layers werewashed with NaHCO₃ aqueous solution and brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/EtOAc (v/v)=3/1) to give the title compound asa pale yellow solid (2.81 g, 70%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 181.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.87-6.83 (m, 1H), 6.81-6.76 (m, 1H),3.96 (d, 3H), 3.11-3.06 (m, 2H), 2.64-2.60 (m, 2H).

Step 6) the Preparation of Compound 33-8

To a suspension of potassium tert-butanolate (1.17 g, 10.41 mmol) intoluene (10.0 mL) was added a solution of compound 33-7 (0.75 g, 4.16mmol) and 1,4-dibromobutane (0.55 mL, 4.58 mmol) in toluene (20.0 mL)via syringe under N₂ at 0° C. At the end of the addition, the mixturewas stirred at 110° C. for 2.5 hrs. After the reaction was completed,the mixture was quenched with water (50 mL). The aqueous phase wasextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=4/1) to give the title compound as a pale yellow solid (0.63 g,65%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 235.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.82-6.81, 6.79 (m, m, 1H), 6.78, 6.75(m, m, 1H), 3.92 (s, 3H), 2.97-2.95 (m, 2H), 2.24-2.12 (m, 2H),1.78-1.58 (m, 4H), 1.56-1.45 (m, 2H).

Step 7) the Preparation of Compound 33-9

To a suspension of compound 33-8 (0.89 g, 3.8 mmol) and triethylsilane(3.7 mL, 23 mmol) was added TFA (8.0 mL) via syringe under N₂ at 0° C.At the end of the addition, the mixture was stirred at 40° C. for 7.0hrs. After the reaction was completed, the mixture was concentrated invacuo. The residue was dissolved in EtOAc (50 mL). The resulting mixturewas washed with saturated Na₂CO₃ aqueous solution and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel column chromatography (PE/EtOAc (v/v)=20/1) to give the titlecompound as pale yellow oil (0.73 g, 87%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 221.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.68-6.60 (m, 2H), 3.81 (d, 3H),2.87-2.84 (m, 2H), 2.77-2.73 (m, 2H), 1.72-1.51 (m, 6H), 1.44-1.33 (m,2H).

Step 8) the Preparation of Compound 33-10

A mixture of compound 33-9 (15.37 g, 69.8 mmol) and NIS (17.2 g, 76.8mmol) in MeCN (200 mL) was added CF₃COOH (0.5 mL, 6.98 mmol) dropwise at0° C. At the end of the addition, the mixture was stirred at 45° C.overnight. After the reaction was completed, the mixture was neutralizedwith saturated NaHCO₃ aqueous solution. The resulting mixture wasextracted with EtOAc (100 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/DCM(v/v)=20/1) to give the title compound (20.54 g, 85%). The compound wascharacterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 347.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.55-6.54, 6.51-6.50 (m, m, 1H), 3.85(s, 3H), 2.86-2.83 (m, 2H), 2.82-2.78 (m, 2H), 1.72-1.53 (m, 6H),1.41-1.31 (m, 2H).

Step 9) the Preparation of Compound 33-11

To a solution of compound 33-10 (1.10 g, 3.17 mmol) in DCM (20.0 mL) wasadded boron tribromide (1.20 mL, 12.67 mmol) dropwise at −78° C. At theend of the addition, the mixture was stirred at −78° C. for 10 mins, andthen stirred at rt for another 1.0 hr. After the reaction was completed,the mixture was quenched with ice-water (50 mL). The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (PE/EtOAc(v/v)=5/1) to give the title compound as pale yellow oil (1.0 g, 95%).The compound was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 333.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 6.57, 6.54 (dd, dd, 1H), 5.48 (brs,1H), 2.83-2.80 (m, 2H), 2.79-2.76 (m, 2H), 1.76-1.56 (m, 6H), 1.47-1.37(m, 2H).

Step 10) the Preparation of Compound 33-12

To a solution of compound 33-11 (1.05 g, 3.16 mmol) in DCM (20.0 mL) wasadded pyridine (2.03 mL, 25.29 mmol) dropwise at 0° C. After the mixturewas stirred for 10 mins, trifluoromethanesulfonic anhydride (3.19 mL,19.97 mmol) was added, and then the mixture was stirred at rt for 1.0hr. After the reaction was completed, the mixture was quenched withice-water (50 mL). The aqueous layer was extracted with DCM (30 mL×3).The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (PE/DCM (v/v)=6/1) to give the title compound ascolorless oil (1.17 g, 80%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.14-7.13, 7.11-7.10 (dd, dd, 1H),2.84-2.78 (m, 4H), 1.76-1.55 (m, 6H), 1.52-1.41 (m, 2H).

Step 11) the Preparation of Compound 33-13

To a mixture of compound 33-12 (3.09 g, 6.65 mmol), compound 1-22 (3.31g, 6.65 mmol), Pd(PPh₃)₄ (0.77 g, 0.79 mmol) and K₂CO₃ (2.77 g, 19.9mmol) were added DME (50.0 mL) and water (10.0 mL) via syringe under N₂.The mixture was stirred at 90° C. for 3.0 hrs. After the reaction wascompleted, the solvent DME was removed. The residue was dissolved inEtOAc (150 mL) and the solution was washed with water (50 mL×3). Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (DCM/MeOH (v/v)=100/1) to give the title compoundas a beige solid (3.54 g, 75%). The compound was characterized by thefollowing spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05, 8.02 (d, d, 1H), 7.49, 7.47 (q,q, 1H), 7.34, 7.31 (d, d, 1H), 6.51-6.50 (m, 1H), 6.07, 6.05 (d, d, 1H),5.10-5.05 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H), 3.60-3.54 (m, 1H),3.24-3.16 (m, 1H), 2.91-2.88 (m, 2H), 2.80-2.77 (m, 2H), 2.46-2.39 (m,1H), 2.15-2.00 (m, 2H), 1.93-1.43 (m, 10H), 1.02, 1.00 (m, m, 3H), 0.93,0.91 (m, m, 3H).

Step 12) the Preparation of Compound 33-14

A mixture of compound 33-13 (5.03 g, 7.1 mmol), compound 1-14-2 (2.72 g,10.7 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.65 g, 0.8 mmol) and KOAc (2.09 g, 21.3mmol) in DMF (30.0 mL) was stirred at 90° C. under N₂. After thereaction was completed, the mixture was cooled to rt, diluted with EtOAc(200 mL) and filtered through a celite pad. The filtrate was washed withwater (60 mL×3) and brine, dried over anhydrous Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE/EtOAc (v/v)=1/3) to give the title compound as a beige solid (3.17g, 65%). The compound was characterized by the following spectroscopicdata:

MS (ESI, pos.ion) m/z: 687.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.04, 8.02 (d, d, 1H), 7.54, 7.52 (q,q, 1H), 7.44-7.43, 7.42-7.41 (dd, dd, 1H), 6.64-6.63 (m, 1H), 6.08, 6.05(d, d, 1H), 5.10-5.05 (m, 1H), 4.30-4.26 (m, 1H), 3.65 (s, 3H),3.60-3.54 (m, 1H), 3.24-3.16 (m, 1H), 3.00-2.97 (m, 2H), 2.85-2.81 (m,2H), 2.46-2.39 (m, 1H), 2.15-2.02 (m, 2H), 1.93-1.73 (m, 2H), 1.72-1.42(m, 6H), 1.32, 1.29 (m, m, 12H), 1.28-1.21 (m, 2H), 1.02, 1.00 (m, m,3H), 0.93, 0.91 (m, m, 3H).

Step 13) the Preparation of Compound 33-15

A suspension of compound 33-14 (0.69 g, 1.0 mmol), compound 33-4 (0.45g, 1.0 mmol), Pd(PPh₃)₄ (0.12 g, 0.1 mmol) and K₂CO₃ (0.35 g, 2.5 mmol)in mixed solvent of DME and H₂O (6 mL, v/v=5/1) was stirred at 90° C.under N₂ for 3.0 hrs. After the reaction was completed, the mixture wasconcentrated in vacuo, and the residue was dissolved in EtOAc (50 mL).The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM/MeOH (v/v)=50/1) to give the title compound as abeige solid (0.70 g, 75%). The compound was characterized by thefollowing spectroscopic data:

MS (ESI, pos.ion) m/z: 466.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.82-8.81 (dd, 1H), 8.04, 8.02 (d, d,1H), 7.74, 7.72 (d, d, 1H), 7.67 (m, 1.5H), 7.65 (d, 0.5H), 7.53, 7.51(q, q, 1H), 7.26, 7.24 (d, d, 1H), 6.63-6.62 (m, 1H), 6.08, 6.06 (d, d,1H), 5.38-5.33 (m, 1H), 5.32, 5.29 (d, d, 1H), 5.10-5.05 (m, 1H),4.41-4.36 (m, 1H), 4.30-4.26 (m, 1H), 3.85-3.78 (m, 1H), 3.69-3.66 (m,1H), 3.65 (s, 3H), 3.63 (s, 3H), 3.60-3.54 (m, 1H), 2.99-2.96 (m, 2H),2.89-2.86 (m, 2H), 2.46-2.39 (m, 1H), 2.30-1.73 (m, 10H), 1.70-1.49 (m,6H), 1.46-1.35 (m, 2H), 1.02, 1.00 (m, m, 3H), 0.97, 0.95 (m, m, 3H),0.93, 0.91 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Example 34

Synthetic Route:

Compounds of Example 34 disclosed herein can be synthesized through theprocedure depicted in Example 1:

Compound 34-2 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 412.7 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 77.78-7.75 (m, 2H), 7.65-7.63 (m, 2H),7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m,1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85(m, 1H), 1.45 (d, 9H).

Compound 34-3 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 392.2 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.78-7.75 (m, 2H), 7.65-7.63 (m, 2H),7.21-7.20 (m, 1H), 5.53-5.15 (m, 2H), 4.49-4.39 (m, 1H), 3.59-3.54 (m,1H), 3.48-3.38 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85(m, 1H), 1.45 (d, 9H).

Compound 34-4 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 292.6 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.76-7.73 (m, 2H), 7.66-7.63 (m, 2H),7.21-7.20 (m, 1H), 5.50-5.22 (m, 2H), 4.49-4.39 (m, 1H), 3.61-3.56 (m,1H), 3.49-3.39 (m, 1H), 2.31-2.21 (m, 2H), 2.12-2.01 (m, 1H), 1.98-1.85(m, 1H).

Compound 34-5 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 450.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H),7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m,1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H),2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.04-1.02 (m, 1H), 0.88-0.86 (d,6H).

Compound 34-6 was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.65-7.60 (m, 2H), 7.47-7.43 (m, 2H),7.22-7.20 (m, 1H), 5.67-5.65 (m, 1H), 5.24-5.22 (m, 1H), 4.34-4.30 (m,1H), 3.85-3.81 (m, 1H), 3.72 (s, 3H), 3.71-3.64 (m, 1H), 3.00 (s, 1H),2.34-2.11 (m, 1H), 2.21-1.95 (m, 5H), 1.45-1.32 (m, 12H), 1.04-1.02 (m,1H), 0.88-0.86 (d, 6H).

Compound 34-7 was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.84-7.82 (m, 1H), 7.69-7.66 (m, 2H),7.57-7.55 (m, 1H), 7.48-7.44 (m, 2H), 7.40-7.36 (m, 1H), 5.41-5.39 (m,1H), 5.29-5.27 (m, 1H), 4.34-4.30 (m, 1H), 3.75-3.70 (m, 1H), 3.69 (s,3H), 3.64-3.62 (m, 1H), 3.20-3.01 (m, 1H), 2.99 (s, 2H), 2.95 (s, 2H),2.25-2.20 (m, 1H), 2.20-2.13 (m, 2H), 1.96-1.94 (m, 1H), 1.78-1.52 (m,8H), 0.88-0.86 (m, 6H).

Compound 34-9 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 470.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d,1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 5.57 (d, 1H, J=8.0 Hz), 4.52-4.49(m, 1H), 4.40-4.36 (m, 1H), 3.89-3.86 (m, 2H), 3.68 (s, 3H), 2.24-2.15(m, 2H), 2.09-2.00 (m, 2H), 1.09 (d, 3H, J=6.0 Hz), 0.97 (d, 3H, J=6.0Hz).

Compound 34-10 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 452.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.31 (s, 1H), 8.07 (d, 1H, J=8.0 Hz),7.79 (d, 1H, J=2.0 Hz), 7.53 (dd, 1H, J=8.0 Hz, 2.0 Hz), 5.78 (d, 1H,J=8.0 Hz), 5.10 (dd, 1H, J=8.0 Hz, 2.0 Hz), 4.33 (t, 1H, J=8.0 Hz),4.14-4.09 (m, 1H), 3.90-3.86 (m, 1H), 3.66 (s, 3H), 2.53-2.51 (m, 1H),2.31-2.29 (m, 1H), 2.18-2.16 (m, 1H), 2.04-1.79 (m, 2H), 0.93 (d, 1H,J=2.0 Hz).

Compound 34-11 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 499.3 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.08 (s, 1H), 8.22 (d, 1H, J=8.0 Hz),8.11 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 5.71 (d, 1H, J=8.0 Hz), 5.17 (d,1H, J=6.0 Hz), 4.35 (t, 1H, J=8.0 Hz), 4.15-4.10 (m, 1H), 3.88-3.86 (m,1H), 3.67 (s, 3H), 2.71-2.67 (m, 1H), 2.34-2.32 (m, 1H), 2.09-1.99 (m,2H), 2.04-1.37 (s, 12H), 0.94-0.89 (m, 6H).

Compound 34-12 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 911.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.21 (s, 1H), 10.46 (s, 1H), 8.28 (s,1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.54-7.51 (m, 2H), 7.46 (s, 2H),7.37-7.33 (m, 2H), 5.70-5.60 (m, 2H), 5.31-5.30 (m, 1H), 5.21-5.20 (m,1H), 4.55-4.35 (m, 2H), 3.95-3.86 (m, 3H), 3.70 (s, 3H), 3.68 (s, 3H),2.98 (s, 4H), 2.69-2.57 (m, 2H), 2.35-2.01 (m, 8H), 2.09-1.99 (m, 2H),0.92-0.84 (m, 12H).

Example 35

Synthetic Route:

Compounds of Example 35 disclosed herein can be synthesized through theprocedure depicted in Example 2:

Compound 35-2 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 320.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.19-7.18 (m, 5H), 5.13-5.12 (m, 2H),4.23, 4.21, 4.19, 4.18 (s, s, s, s, 2H), 4.03-3.97 (m, 1H), 3.59, 3.58(s, s, 2H), 3.50-3.43 (m, 1H), 3.32-3.23 (m, 1H), 2.08-1.93 (m, 2H),1.82-1.70 (m, 2H), 1.29-1.25 (t, 3H, J=8.0 Hz).

Compound 35-3 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 428.9 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd,1H), 7.45, 7.43 (dd, dd, 1H), 7.28-7.22 (m, 5H), 6.58 (t, 1H), 5.14-5.13(m, 2H), 4.98-4.94 (m, 1H), 3.64-3.57 (m, 1H), 3.43-3.36 (m, 1H),2.26-2.17 (m, 1H), 2.09-1.83 (m, 3H).

Compound 35-4 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 293.5 [M+H]⁺.

Compound 35-5 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 450.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.13-8.12 (m, 1H), 7.60, 7.58 (dd, dd,1H), 7.45, 7.43 (dd, dd, 1H), 6.64 (m, 1H), 5.32, 5.29 (dd, dd, 1H),5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.49 (m, 1H),3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 0.97, 0.95 (m,m, 3H), 0.91, 0.89 (m, m, 3H).

Compound 35-6 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 498.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.48-8.47 (m, 1H), 8.00, 7.99 (dd, dd,1H), 7.47, 7.45 (dd, dd, 1H), 6.76 (m, 1H), 5.32, 5.29 (dd, dd, 1H),5.18-5.13 (m, 1H), 4.27-4.22 (m, 1H), 3.63 (s, 3H), 3.56-3.50 (m, 1H),3.19-3.11 (m, 1H), 2.13-2.00 (m, 1H), 1.93-1.62 (m, 4H), 1.23, 1.20 (m,m, 12H), 0.97, 0.96 (m, m, 3H), 0.91, 0.89 (m, m, 3H).

Compound 35-7 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 455.8 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.05 (m, 1H), 7.72-7.71 (m, 1H),7.70-7.69 (m, 1H), 7.62 (dd, 1H), 7.60-7.56 (m, 4H), 7.52-7.49 (m, 2H),7.00-6.99 (m, 1H), 5.32, 5.29 (dd, dd, 2H), 5.23-5.19 (m, 1H), 5.18-5.13(m, 1H), 4.41-4.36 (m, 1H), 4.27-4.22 (m, 1H), 3.85-3.78 (m, 1H),3.69-3.64 (m, 1H), 3.63 (s, 6H), 3.56-3.50 (m, 1H), 3.19-3.11 (m, 1H),2.93-2.88 (m, 4H), 2.30-1.35 (m, 18H), 0.97, 0.95 (m, m, 6H), 0.90, 0.89(m, m, 6H).

Example 36

Synthetic Route:

Compounds of Example 36 disclosed herein can be synthesized through theprocedure depicted in Example 3:

Compound 36-1 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 456.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.08-8.07 (m, 1H), 7.65 (m, 2H), 6.40(m, 1H), 4.19-4.15 (m, 1H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H),2.28-2.09 (m, 2H), 1.93-1.72 (m, 2H), 1.68 (d, 6H), 1.40 (s, 9H).

Compound 36-2 was characterized by the following spectroscopic data:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.07, 7.05 (dd, dd, 1H), 7.04, 7.02(dd, dd, 1H), 6.77 (q, 1H), 6.40 (m, 1H), 4.11-4.07 (m, 1H), 3.98 (brs,2H), 3.52-3.46 (m, 1H), 3.35-3.28 (m, 1H), 2.28-2.09 (m, 2H), 1.93-1.73(m, 2H), 1.69 (d, 6H), 1.40 (s, 9H).

Compound 36-3 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 408.1 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H),7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.14 (brs, 1H), 4.81-4.77 (m,1H), 3.52-3.46 (m, 1H), 3.41-3.34 (m, 1H), 2.52-2.45 (m, 1H), 2.18-2.09(m, 1H), 1.95-1.86 (m, 1H), 1.85-1.75 (m, 1H), 1.65-1.64 (m, 3H),1.62-1.61 (m, 3H), 1.42 (s, 9H).

Compound 36-4 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 308.5 [M+H]⁺.

Compound 36-5 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 465.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.30-7.29, 7.27-7.26 (d, d, 1H),7.24-7.22 (m, 1H), 6.84, 6.81 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14(brs, 1H), 4.65-4.61 (m, 1H), 4.32-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54(m, 1H), 3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H),1.90-1.82 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m,3H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m, 3H).

Compound 36-6 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 513.5 [M+H]⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67, 7.65 (d, d, 1H), 7.48-7.47 (m,1H), 7.26, 7.24 (d, d, 1H), 5.32, 5.29 (d, d, 1H), 5.14 (brs, 1H),4.65-4.61 (m, 1H), 4.33-4.28 (m, 1H), 3.63 (s, 3H), 3.60-3.54 (m, 1H),3.28-3.20 (m, 1H), 2.40-2.32 (m, 1H), 2.10-1.98 (m, 2H), 1.90-1.82 (m,1H), 1.80-1.70 (m, 1H), 1.65-1.64 (m, 3H), 1.62-1.61 (m, 3H), 1.25-1.24(q, 6H), 1.22-1.21 (q, 6H), 0.97, 0.95 (m, m, 3H), 0.90, 0.89 (m, m,3H).

Compound 36-7 was characterized by the following spectroscopic data:

MS (ESI, pos.ion) m/z: 463.5 [M+2H]²⁺; and

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.69 (brs, 2H), 7.60-7.57 (m, 3H),7.52-7.47 (m, 4H), 7.40-7.38 (dd, dd, 1H), 7.37-7.35 (d, d, 1H), 7.19,7.17 (d, d, 1H), 5.32, 5.29 (d, d, 2H), 5.23-5.19 (m, 1H), 4.65-4.61 (m,1H), 4.41-4.28 (m, 2H), 3.85-3.78 (m, 1H), 3.69-3.64 (m, 1H), 3.63 (s,6H), 3.60-3.54 (m, 1H), 3.28-3.20 (m, 1H), 3.04-3.00 (m, 2H), 2.92-2.88(m, 2H), 2.40-2.32 (m, 1H), 2.30-1.92 (m, 7H), 1.90-1.82 (m, 1H),1.80-1.71 (m, 1H), 1.69-1.51 (m, 12H), 1.46-1.35 (m, 2H), 0.97, 0.95 (m,m, 6H), 0.90, 0.89 (m, m, 6H).

BIOLOGICAL ACTIVITY

HCV Replicon System was utilized as an evaluation model in the presentdisclosure for verifying the effects of the compounds disclosed hereinon HCV. An HCV Replicon assay was first described in Science, 1999, 285(5424), 110-3. HCV Replicon System is one of the most important toolsfor research on HCV RNA replication, pathogenicity and persistent ofvirus, for example, 5′-NCR minimum areas is necessary for HCV RNAreplication that was proved by using replicon, and HCV Replicon Systemwas utilized successfully as an evaluation model of antiviral drugs. Todetermine the potential anti-HCV effects of the test compounds,luciferase assay and antibiotic Neomycin resistance gene were testedaccording to the method described in Science. 1999 Jul. 2; 285 (5424),110-3 and J. Virol. 2003 March; 77 (5),3007-19.

In a word, the compounds disclosed herein were tested by using humanhepatic carcinoma cell line which is transfected stably HCV GT1a, GT1bor GT2a replicon respectively, and resistant cells Y93H, L31F, P32L orI302V and wild-type cells HCV 1b. HCV Replicon System disclosed hereincontaining Neomycin resistance gene and Luciferase Reporter Gene, thelevel of HCV replication in host cells is characterized by theexpression level of the NEO gene expression level or Luciferase ReporterGene, and the effects of the compounds herein inhibit HCV replicationcan be evaluated. In this article, a real-time quantitative polymerasechain reaction (qPCR) method was used to detect NEO gene expressionlevel, and chemiluminescence method was used to test Luciferase ReporterGene expression level.

Operating Procedure:

1. Test Method for Measuring EC₅₀ of the Compounds Base on LuciferaseAssay.

The Huh-7 cells transfected with HCV replicons system were seeded into96-well plates (8,000 cells in 125 μL/well) respectively; each testcompound was diluted to desired concentration using 5-fold serialdilutions protocol, 10 doses in duplicate, and added to wells with POD™810 Plate Assembler. The plates were incubated in a CO₂ incubator for 72hours; after that, 40 μL of Luciferase assay substrate (PromegaBright-Glo) was added to each well, and detected by a chemiluminescencedetection system (Topcount Microplate Scintillation and LuminescenceCounter) 5 minutes later; the EC₅₀ (half-maximal effectiveconcentration, concentration for 50% of maximal effect) values of testcompounds were analyzed by GraphPad Prism software, respectively. Inthis paper, experiments were repeated twice and set the holes withoutcompounds as negative control.

2. Test Method for Measuring EC₅₀ of the Compounds by DetectingAntibiotic G418 Resistance Gene NEO Gene.

The Huh-7 cells transfected with HCV replicons system were seeded into96-well plates (8,000 cells in 125 μL/well) respectively; each testcompound was diluted to desired concentration using 5-fold serialdilutions protocol, 10 doses in duplicate, and added to each well withPOD™ 810 Plate Assembler; the cells were incubated in a CO₂ incubatorfor 72 hours; and detected the expression level of the NEO geneexpression with real-time qualitative PCR later; The EC₅₀ (half-maximaleffective concentration, concentration for 50% of maximal effect) valuesof test compounds were analyzed by GraphPad Prism software,respectively. In this paper, experiments were repeated twice and set theholes without compounds as negative control.

3. Results

The test compounds of the present disclosure can be effective againstthe HCV 1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a and 6a genotypes according to theexperiment data, and EC₅₀ ranges of the test compounds against HCV 1bare 1 pM-99 nM; Table 2 shows the EC₅₀ values of representativecompounds of the present disclosure against the HCV 1a and HCV 1bgenotypes.

TABLE 2 Example 1a (nM) 1b (nM) 1 0.760 0.042 2 1.276 0.087 3 0.5370.040 4 0.089 0.016 5 0.078 0.023 6 0.109 0.077 7 0.210 0.103 8 0.9820.065 9 0.439 0.072 10 1.275 0.438 11 0.068 0.032 12 0.380 0.049 132.067 0.273 14 0.884 0.013 15 0.206 0.142 16 0.089 0.036 17 0.023 0.00618 0.326 0.065 19 4.769 0.436 20 3.672 0.685 21 0.080 0.029 22 0.5610.072 23 0.310 0.047 24 0.475 0.099 25 0.829 0.103 26 0.727 0.216 271.529 0.323 28 1.104 0.763 29 0.061 0.009 30 0.336 0.052 31 5.873 0.53932 10.285 0.446 33 0.078 0.022 34 0.641 0.055 35 10.552 0.103 36 0.4380.062

According to the experimental results of wild-type HCV 1b and resistancecells Y93H, L31F, P32L, I302V, and the simulation results of molecularmodeling and docking show that compounds disclosed herein play anexcellent anti-HCV role, which suggest a novel anti-HCV mechanism byinterfering with HCV NS5A protein.

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A. Thecompounds of the present disclosure may inhibit multiple genotypes ofHCV.

Reference throughout this specification to “an embodiment,” “someembodiments,” “one embodiment”, “another example,” “an example,” “aspecific example,” or “some examples,” means that a particular feature,structure, material, or characteristic described in connection with theembodiment or example is included in at least one embodiment or exampleof the present disclosure. Thus, the appearances of the phrases such as“in some embodiments,” “in one embodiment”, “in an embodiment”, “inanother example,” “in an example,” “in a specific example,” or “in someexamples,” in various places throughout this specification are notnecessarily referring to the same embodiment or example of the presentdisclosure. Furthermore, the particular features, structures, materials,or characteristics may be combined in any suitable manner in one or moreembodiments or examples.

Although explanatory embodiments have been shown and described, it wouldbe appreciated by those skilled in the art that the above embodimentscannot be construed to limit the present disclosure, and changes,alternatives, and modifications can be made in the embodiments withoutdeparting from spirit, principles and scope of the present disclosure.

1. A compound having Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, a metabolite, a pharmaceutically acceptable salt ora prodrug thereof, wherein: A is a single bond, alkylene, alkenylene,cycloalkylene, heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═)_(r)—N(R⁵)CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—, or—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶, or CR⁷R^(7a); X⁴ is(CR⁷R^(7a))_(n), —Y¹═Y²—, O, S or NR⁶; W is a C₃₋₈ carbocyclyl or C₂₋₁₀heterocyclyl ring; each Y¹ and Y² is independently N or CR⁷; Z is—(CH₂)_(a)—, —CH═CH—, —N═CH—, —(CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or—(CH₂)_(a)—O—(CH₂)_(b); each c and d is independently 1 or 2; each a, b,n and p is independently 0, 1, 2 or 3; each r is independently 0, 1 or2; each of Q¹ and Q² is independently NR⁶, O, S, C(═O) or(CR⁷R^(7a))_(e); each e and f is independently 0, 1, 2, 3 or 4; each ofX and X′ is independently N or CR⁷; each of Y and Y′ is independently H,deuterium, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, a monovalent group derived from α-amino acid or anoptically isomer thereof, or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;each Q⁴ and U is independently —C(═O)—, —C(═S)—, —S(═O)— or —S(═O)₂—;each t is independently 0, 1, 2, 3 or 4; each k is independently 0, 1 or2; each of R¹, R², R³ and R⁴ is independently H, deuterium, alkyl,heteroalkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl; orR¹ and R², together with X—CH they are attached to, optionally form a3-8 membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; or R³and R⁴, together with X′—CH they are attached to, optionally form a 3-8membered heterocycle or carbocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂ fusedheterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle; each R⁵is independently H, deuterium, hydroxy, alkyl, heteroalkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—,alkyl-C(═O)—, carbamoyl, alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—,alkyl-S(═O)_(r)— or aminosulfonyl; each R^(5a) is independently H,deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—,—C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—,R^(13a)R¹³N-alkyl, R¹³S(═O)-alkyl, R¹³R^(13a)N—C(═O)-alkyl,R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy, R¹³R^(13a)N—C(═O)-alkoxy, aryl,heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino,heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy,heteroarylalky, arylalkoxy, heteroarylalkoxy, heterocyclyloxy,heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy,alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl,alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, aliphatic, haloaliphatic, hydroxyaliphatic,aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic,alkylthioaliphatic, arylaliphatic, heteroarylaliphatic,heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic,heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic,heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl,heterocyclyl or carbocyclyl; each R^(6a) is independently H, deuterium,hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R^(13a)R¹³N—,—C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—,R^(13a)R¹³N-alkyl, R¹³S(═O)-alkyl, R¹³R^(13a)N—C(═O)-alkyl,R^(13a)R¹³N-alkoxy, R¹³S(═O)-alkoxy, R¹³R^(13a)N—C(═O)-alkoxy, aryl,heteroaryl, alkoxy, alkylamino, alkyl, haloalkyl, alkenyl, alkynyl,heterocyclyl, cycloalkyl, mercapto, nitro, aralkyl, arylamino,heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy,heterocyclylalkoxy, heterocyclylamino, alkylacyl, alkylacyloxy,alkoxyacyl, alkylsulfonyl, alkoxysulfonyl, alkylsulfinyl,alkylsulfonyloxy, alkylsulfinyloxy, heterocyclylalkylamino or aryloxy;each R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I,aliphatic, heteroalkyl, haloaliphatic, hydroxyaliphatic, aminoaliphatic,alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;each R⁸ and R^(8a) is independently H, deuterium, hydroxy, cyano, nitro,F, Cl, Br, I, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, aralkyl, alkoxy, alkyl-OC(═O)—, alkyl-C(═O)—, carbamoyl,alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)— or aminosulfonyl;each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,haloalkyl, hydroxyalkyl, heteroarylalkyl, heterocyclylalkyl orcycloalkylalkyl; each R¹² is independently R^(13a)R¹³N—, —C(═O)R¹³,—C(═S)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R¹³, —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a) N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—,alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl oraralkyl; or R¹¹ and R¹² are optionally joined to form a 4-7 memberedring; and and each R¹³ and R^(13a) is independently H, deuterium, alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or aralkyl; withthe proviso that where R¹³ and R^(13a) are bonded to the same nitrogenatom, R¹³ and R^(13a), together with the nitrogen atom they are attachedto, optionally form a substituted or unsubstituted 3-8 membered ring,spiro bicyclic ring or fused bicyclic ring; wherein each of alkylene,alkenylene, cycloalkylene, heterocycloalkylene,—(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—NR¹¹—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹²,—[U—(CR⁹R^(9a))_(t)—NR¹⁰—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²,NR⁶, CR⁷R^(7a), CR⁷, —(CH₂)_(a)—, —CH═CH—, —N═CH—,—(CH₂)_(a)—N(R⁵)—(CH₂)_(b)—, —(CH₂)_(a)—O—(CH₂)_(b)—, R^(13a)R¹³N—,—C(═O)R¹³, —C(═S)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, alkyl-OC(═O)—,alkyl-C(═O)—, alkyl-OS(═O)_(r)—, alkyl-S(═O)_(r)O—, alkyl-S(═O)_(r)—,R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R^(13a)R¹³N-alkyl,R¹³S(═O)-alkyl, R¹³R^(13a)N—C(═O)-alkyl, R^(13a)R¹³N-alkoxy,R¹³S(═O)-alkoxy, R¹³R^(13a)N—C(═O)-alkylamino, alkyl, heteroalkyl,carbocyclyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,α-amino acid, C₅₋₁₂ fused bicycle, C₅₋₁₂ fused heterobicycle, C₅₋₁₂spiro bicycle, C₅₋₁₂ spiro heterobicycle, alkoxy, aliphatic,haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic,alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic,heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic,aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic,arylaminoaliphatic, heterocyclylaminoaliphatic,cycloalkylaminoaliphatic, haloalkyl, alkenyl, alkynyl, arylamino,heteroarylamino, arylalkylamino, heteroarylalkylamino, heteroaryloxy,heteroarylalkyl, arylalkoxy, heteroarylalkoxy, heterocyclyloxy,heterocyclylalkoxy, heterocyclylamino, heterocyclylalkylamino andaryloxy is optionally substituted with one or more substituentsindependently selected from hydroxy, deuterium, amino, halo, cyano,aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl,alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(═O),carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(═O)—,alkyl-C(═O)—, alkyl-S(═O)—, alkyl-S(═O)₂—, hydroxy-substitutedalkyl-S(═O)—, hydroxy-substituted alkyl-S(═O)₂— or carboxyl-substitutedalkoxy.
 2. (canceled)
 3. The compound according to claim 1, wherein

wherein each X³ and X⁵ is independently O, S, NR⁶, C(═O) or CR⁷R^(7a);each X⁶ is independently CR⁷R^(7a), O, S or NR⁶; each Y¹ and Y² isindependently N or CR⁷; each Q¹ and Q² is independently NR⁶, O, S, C(═O)or (CR⁷R^(7a))_(e); each e and f is independently 0, 1, 2, 3 or 4; eachR^(5a) is independently H, deuterium, oxo(═O), hydroxy, amino, F, Cl,Br, I, cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a),—OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a),—N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—,R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl, C₁₋₆ alkylacyloxy, C₁₋₆alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkoxysulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyloxy, C₁₋₆ alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₆₋₁₀ aryl, —CF₃, —OCF₃, mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀cycloalkyl or C₆₋₁₀ aryloxy; each R⁶ is independently H, deuterium,R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—,R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—, R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl,C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl; each R⁷and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl,C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₁₀ carbocyclyl; and eachR¹³ and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ andR^(13a) are bonded to the same nitrogen atom, R¹³ and R^(13a), togetherwith the nitrogen atom they are attached to, optionally form asubstituted or unsubstituted 3-8 membered ring, spiro bicyclic ring orfused bicyclic ring; or wherein

wherein each Y¹ and Y² is independently N or CH; each X⁶ isindependently CR⁷R^(7a), O, S, or NR⁶; each R^(5a) is independently H,deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—,—C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂NR^(13a)—, C₁₋₆ alkylacyl,C₁₋₆ alkylacyloxy, C₁₋₆ alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkoxysulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃,mercapto, nitro or C₁₋₆ alkylamino; R⁶ is H, deuterium,R¹³R^(13a)NC(═O)—, R¹³OC(═O)—, R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—,R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—, R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl,C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl, C₃₋₈ cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; and eachof R⁷ and R^(7a) is independently H, deuterium, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl-C₁₋₆-alk, C₆₋₁₀aryloxy-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀ arylamino-C₁₋₆-alkyl, C₂₋₁₀heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀ cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; each R¹³and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl,C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl orC₆₋₁₀-alkyl; with the proviso that where R¹³ and R^(13a) are bonded tothe same nitrogen atom, R¹³ and R^(13a), together with the nitrogen atomthey are attached to, optionally form a substituted or unsubstituted 3-8membered ring, spiro bicyclic ring or fused bicyclic ring.
 4. (canceled)5. The compound according to claim 1, wherein A is a single bond, C₁₋₆alkylene, C₂₋₆ alkenylene, C₃₋₈ cycloalkylene, C₂₋₁₀heterocycloalkylene, —(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—(N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—, or—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

wherein each X¹ and X² is independently O, S, NR⁶ or CR⁷R^(7a); Q⁴ is—C(═O)—, —S(═O)— or —S(═O)₂—; each e is independently 0, 1, 2, 3 or 4;each Y¹ and Y² is independently N or CR⁷; Z is —(CH₂)_(a)—, —CH═CH—,—N═CH—, —(CH₂)_(a)—N(R⁵)—(CH₂)_(b)— or —(CH₂)_(a)—O—(CH₂)_(b)—; each cand d is independently 1 or 2; each a b n and p is independently 0, 1, 2or 3; each r is independently 0, 1 or 2; each R⁵ is independently H,deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl; R⁶ is H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl,C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl; each R^(6a) is independently H,deuterium, hydroxy, amino, F, Cl, Br, I, cyano, oxo(═O), R^(13a)R¹³N—,—C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—,R^(13a)R¹³N—C₁₋₆-alkyl, R¹³S(═O)—C₁₋₆-alkyl,R¹³R^(13a)N—C(═O)—C₁₋₆-alkyl, R^(13a)R¹³N—C₁₋₆-alkoxy,R¹³S(═O)—C₁₋₆-alkoxy, R¹³R^(13a)N—C(═O)—C₁₋₆-alkoxy, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl,mercapto, nitro, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₆₋₁₀ arylamino, C₁₋₉heteroarylamino or C₆₋₁₀ aryloxy; each R⁷ and R^(7a) is independently H,deuterium, F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆alkylamino-C₁₋₆-alkyl, C₁₋₆ alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl,C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₃₋₁₀cycloalkyl-C₁₋₆-alkyl, C₆₋₁₀ aryloxy-C₁₋₆-alkyl, C₂₋₁₀heterocyclyloxy-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyloxy-C₁₋₆-alkyl, C₆₋₁₀arylamino-C₁₋₆-alkyl, C₂₋₁₀ heterocyclylamino-C₁₋₆-alkyl, C₃₋₁₀cycloalkylamino-C₁₋₆-alkyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₈ carbocyclyl; each R¹³ and R^(13a) is independentlyH, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; withthe proviso that where R¹³ and R^(13a) are bonded to the same nitrogenatom, R¹³ and R^(13a), together with the nitrogen atom they are attachedto, optionally form a substituted or unsubstituted 3-8 membered ring,spiro bicyclic ring or fused bicyclic ring; and each R⁸ and R^(8a) isindependently H, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C₁₋₆alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—,C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl; orwherein A is a single bond, —CH₂—, —(CH₂)₂—, —CH═CH—, —CH═CH—CH₂—,—N(R⁵)—, —C(═O)—, —C(═S)—, —C(═O)—O—, —C(═O)N(R⁵)—, —OC(═O)N(R⁵)—,—OC(═O)O—, —N(R⁵)C(═O)N(R⁵)—, —(R⁵)N—S(═O)₂—, —S(═O)₂—, —OS(═O)₂—,—(R⁵)N—S(═O)—, —S(═O)—, —OS(═O)—, or A is

A′ is

wherein, X¹ is O or S; Y¹ is N or CH; each e is independently 0, 1, 2 or3; each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₈ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆-alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl; each R⁶ is independently H,deuterium, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆aminoalkyl, C₁₋₆ alkoxy-C₁₋₆-alkyl, C₁₋₆ alkylamino-C₁₋₆-alkyl, C₁₋₆alkylthio-C₁₋₆-alkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl, C₆₋₁₀aryl, C₂₋₁₀ heterocyclyl or C₃₋₈ carbocyclyl; each R^(6a) isindependently H, deuterium, hydroxy, amino, F, Cl, Br, I, cyano,oxo(═O), R^(13a)R¹³N—, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, mercapto or nitro; and each R¹³and R^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl,C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl orC₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ and R^(13a) arebonded to the same nitrogen atom, R¹³ and R^(13a), together with thenitrogen atom they are attached to, optionally form a substituted orunsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclicring.
 6. (canceled)
 7. The compound according to claim 1, wherein eachof R¹, R², R³ and R⁴ is independently H, C₁₋₈ alkyl, C₁₋₈ heteroalkyl,C₆₋₁₀ aryl-C₁₋₆-alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₁₋₉heteroaryl or C₆₋₁₀ aryl; or R¹ and R², together with X—CH they areattached to, optionally form a 3-8 membered heterocycle or carbocycle,C₅₋₁₂ fused bicycle, C₅₋₁₂ fused heterobicycle, C₅₋₁₂ spiro bicycle orC₅₋₁₂ spiro heterobicycle; or R³ and R⁴, together with X′—CH they areattached to, optionally form a 3-8 membered heterocycle or carbocycle,C₅₋₁₂ fused bicycle, C₅₋₁₂ fused heterobicycle, C₅₋₁₂ spiro bicycle orC₅₋₁₂ spiro heterobicycle; or wherein R¹ and R², together with X—CH theyare attached to, or R³ and R⁴, together with X′—CH they are attached to,optionally form a 3-8 membered heterocycle, C₅₋₁₂ fused bicycle, C₅₋₁₂fused heterobicycle, C₅₋₁₂ spiro bicycle or C₅₋₁₂ spiro heterobicycle;or wherein R¹, R² and Y—X—CH together form one of the followingmonovalent groups:

wherein R³, R⁴ and Y′—X′—CH together form one of the followingmonovalent groups:

wherein each R¹⁵ is independently H, deuterium, oxo(═O), F, Cl, Br, I,cyano, hydroxy, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃alkylamino, C₁₋₃ alkylthio, C₆₋₁₀ arylamino, C₆₋₁₀ aryloxy, C₁₋₉heteroaryl, C₁₋₉ heteroaryloxy, C₁₋₉ heteroaryl-C₁₋₃-alkyl or C₂₋₁₀heterocyclyl; each R⁶ is independently H, deuterium, C₁₋₃ alkyl, C₁₋₃haloalkyl, C₁₋₃ hydroxyalkyl, C₁₋₃ aminoalkyl, C₁₋₃ alkoxy-C₁₋₃-alkyl,C₁₋₃ alkylamino-C₁₋₃-alkyl, C₁₋₃ alkylthio-C₁₋₃-alkyl, C₆₋₁₀aryl-C₁₋₃-alkyl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈carbocyclyl; and each n₁ and n₂ is independently 1, 2, 3 or
 4. 8-10.(canceled)
 11. The compound according to claim 1 having formula (II):

wherein,

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4; each X³ and X⁵ isindependently O, S, NR⁶, C(═O) or CR⁷R^(7a); each Y¹ and Y² isindependently N or CR⁷; A is a single bond, C₁₋₆ alkylene, C₂₋₆alkenylene, C₃₋₈ cycloalkylene, C₂₋₁₀ heterocycloalkylene,—(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

X¹ is O, S, NR⁶ or CR⁷R^(7a); each R⁵ is independently H, deuterium,hydroxy, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆ alkyl-C(═O)—, carbamoyl, C₁₋₆alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—, C₁₋₆ alkyl-S(═O)_(r)— oraminosulfonyl; each R^(5a) and R^(6a) is independently H, deuterium,oxo(═O), hydroxy, amino, F, Cl, Br, I, cyano, R^(13a)R¹³N—,—C(═O)NR¹³R^(13a), —OC(═O)NR³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl,C₁₋₆ alkylacyloxy, C₁₋₆ alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkoxysulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃,mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀ cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl; each of R⁷ and R^(7a) isindependently H, deuterium, F, Cl, Br, I, C₁₋₆ aliphatic, C₂₋₆heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆ alkylamino-C₁₋₆-aliphatic,C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl; each R⁸ and R^(8a) is independentlyH, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl; each R¹³ and R^(13a) isindependently H, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl or C₆₋₁₀aryl-C₁₋₆-alkyl; with the proviso that where R¹³ and R^(13a) are bondedto the same nitrogen atom, R¹³ and R^(13a), together with the nitrogenatom they are attached to, optionally form a substituted orunsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclicring; each n and p is independently 0, 1, 2 or 3; each r isindependently 0, 1 or 2; and each of Y₄ and Y₄′ is independently asingle bond, O, S, —(CH₂)_(n)—, —CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—,—CF₂—, —CHR^(5a)—, —CR^(5a)R^(6a)—, —CH₂S(═O)_(r), or —CH₂N(R⁶)—. 12.The compound according to claim 1 having formula (II′):

wherein

wherein each Q¹ and Q² is independently NR⁶, O, S, C(═O) or (CH₂)_(e);each e and f is independently 0, 1, 2, 3 or 4; each X³ and X⁵ isindependently O, S, NR⁶, C(═O) or CR⁷R^(7a); each X⁶ is independentlyCH₂, O, S or NR⁶; A is a single bond, C₁₋₆ alkylene, C₂₋₆ alkenylene,C₃₋₈ cycloalkylene, C₂₋₁₀ heterocycloalkylene,—(CR⁸R^(8a))_(n)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—N(R⁵)—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—N(R⁵)—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—C(═O)—O—(CR⁸R^(8a))—,—(CR⁸R^(8a))_(n)—N(R⁵)—S(═O)_(r)—N(R⁵)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—S(═O)_(r)—O—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═O)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—C(═S)—(CR⁸R^(8a))_(p)—,—(CR⁸R^(8a))_(n)—N(R⁵)—C(═O)—O—(CR⁸R^(8a))_(p)—, or A is

A′ is

each R⁵ is independently H, deuterium, hydroxy, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl; each R^(5a) and R^(6a) isindependently H, deuterium, oxo(═O), hydroxy, amino, F, Cl, Br, I,cyano, R^(13a)R¹³N—, —C(═O)NR¹³R^(13a), —OC(═O)NR¹³R^(13a), —OC(═O)OR¹³,—N(R¹³)C(═O)NR¹³R^(13a), —N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a),R¹³R^(13a)N—S(═O)₂—, R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, C₁₋₆ alkylacyl,C₁₋₆ alkylacyloxy, C₁₋₆ alkoxyacyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkoxysulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyloxy, C₁₋₆alkylsulfinyloxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₆₋₁₀ aryl, —CF₃, —OCF₃,mercapto, nitro, C₁₋₆ alkylamino, C₃₋₁₀ cycloalkyl or C₆₋₁₀ aryloxy;each R⁶ is independently H, deuterium, R¹³R^(13a)NC(═O)—, R¹³OC(═O)—,R¹³C(═O)—, R¹³R^(13a)NS(═O)—, R¹³OS(═O)—, R¹³S(═O)—, R¹³R^(13a)NS(═O)₂—,R¹³OS(═O)₂—, R¹³S(═O)₂—, C₁₋₆ aliphatic, C₁₋₆ alkoxy-C₁₋₆-aliphatic,C₁₋₆ alkylamino-C₁₋₆-aliphatic, C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₁₋₉heteroaryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl; each of R⁷ and R^(7a) isindependently H, deuterium, F, Cl, Br, I, C₁₋₆ aliphatic, C₂₋₆heteroalkyl, C₁₋₆ alkoxy-C₁₋₆-aliphatic, C₁₋₆ alkylamino-C₁₋₆-aliphatic,C₆₋₁₀ aryl-C₁₋₆-aliphatic, C₂₋₁₀ heterocyclyl-C₁₋₆-aliphatic, C₃₋₁₀cycloalkyl-C₁₋₆-aliphatic, C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₂₋₁₀heterocyclyl or C₃₋₁₀ carbocyclyl; each R⁸ and R^(8a) is independentlyH, deuterium, hydroxy, cyano, nitro, F, Cl, Br, I, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl-OC(═O)—, C₁₋₆alkyl-C(═O)—, carbamoyl, C₁₋₆ alkyl-OS(═O)_(r)—, C₁₋₆ alkyl-S(═O)_(r)O—,C₁₋₆ alkyl-S(═O)_(r)— or aminosulfonyl; each R¹³ and R^(13a) isindependently H, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl or C₆₋₁₀aryl-C₁₋₆-alkyl; with the proviso that where R¹³ and R^(13a) are bondedto the same nitrogen atom, R¹³ and R^(13a), together with the nitrogenatom they are attached to, optionally form a substituted orunsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclicring; each n and p is independently 0, 1, 2 or 3; each r isindependently 0, 1 or 2; and each of Y₄ and Y₄′ is independently asingle bond, O, S, —(CH₂)_(n)—, —CH═CH—, —S(═O)_(r)—, —CH₂O—, —CH₂S—,—CF₂—, —CR^(5a)R^(6a)—, CHR^(5a)—, —CH₂S(═O)_(r), or —CH₂N(R⁶)—.
 13. Thecompound according to claim 11 having formula (III), or Formula (IV), orFormula (V):

wherein each of Q² and Q³ is independently O, S, C(═O), NR⁶, or CH₂; andwherein e is 1, 2, 3 or
 4. 14-15. (canceled)
 16. The compound accordingto claim 12 having formula (III′), or Formula (IV′), or Formula (V′):

wherein each of Q² and Q³ is independently O, S, C(═O), NR⁶, or CH₂; andwherein e is 1, 2, 3 or
 4. 17-18. (canceled)
 19. The compound accordingto claim 1, wherein, each of Y and Y′ is independently a monovalentgroup derived from an α-amino acid which is optionally substituted withone or more substituents independently selected from deuterium, F, Cl,Br, I, hydroxy or cyano; or wherein the α-amino acid is isoleucine,leucine, lysine, methionine, phenylalanine, threonine, tryptophane,valine, alanine, asparagine, aspartic acid, glutamic acid, glutamine,proline, serine, p-tyrosine, arginine, histidine, cysteine, glycine,sarcosine, N,N-dimethylglycine, homoserine, norvaline, norleucine,ornithine, homocysteine, homophenylalanine, phenylglycine, o-tyrosine,m-tyrosine or hydroxyproline; or wherein the α-amino acid is in the Dconfiguration; or wherein the α-amino acid is in the L configuration.20-22. (canceled)
 23. The compound according to claim 1 wherein each ofY and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²,—U—(CR⁹R^(9a))_(t)—R¹² or—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²; or wherein each of Y andY′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—[C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—R¹²; or wherein each of Yand Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—C(═O)—R¹³; or wherein eachof Y and Y′ is independently —C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—C(═O)—R¹³; orwherein each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—(CR⁹R^(9a))_(t)—C(═O)—O—R¹³; or whereineach of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—C(═O)—O—R¹³; or wherein each of Y and Y′is independently —U—(CR⁹R^(9a))_(t)—R¹²; or wherein each of Y and Y′ isindependently —C(═O)—(CR⁹R^(9a))_(t)—R¹²; or wherein each of Y and Y′ isindependently—[U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)]_(k)—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—U—(CR⁹R^(9a))O—(CR⁹R^(9a))_(t)—R¹²; or wherein each of Y and Y′ is independently—C(═O)—(CR⁹R^(9a))_(t)—N(R¹⁰)—(CR⁹R^(9a))_(t)—C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²;or wherein each of Y and Y′ is independently—U—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))—R¹²; or wherein each of Y and Y′ isindependently —C(═O)—(CR⁹R^(9a))_(t)—O—(CR⁹R^(9a))_(t)—R¹²; or whereineach of Y and Y′ is independently —C(═O)—(CR⁹R^(9a))_(t)—N(R¹¹)—R¹²,wherein R¹¹ and R¹², together with the atom they are attached to, form a4-7 membered ring. 24-43. (canceled)
 44. The compound according to claim23, wherein each R⁹, R^(9a), R¹⁰ and R¹¹ is independently H, deuterium,C₁₋₆ alkyl, C₂₋₆ heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl,C₆₋₁₀ aryl, C₁₋₉ heteroaryl, C₆₋₁₀ aryl-C₁₋₆-alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkylor C₃₋₈ cycloalkyl-C₁₋₆-alkyl; each R¹² is independently R^(13a)R¹³N—,—C(═O)R¹³, —C(═S)R¹³, —C(═O)—O—R¹³, —C(═O)NR¹³R^(13a),—OC(═O)NR¹³R^(13a), —OC(═O)OR¹³, —N(R¹³)C(═O)NR¹³R^(13a),—N(R¹³)C(═O)OR^(13a), —N(R¹³)C(═O)—R^(13a), R¹³R^(13a)N—S(═O)₂—,R¹³S(═O)₂—, R¹³S(═O)₂N(R^(13a))—, R¹³OS(═O)₂—, C₁₋₆ alkyl, C₂₋₆heteroalkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl or C₆₋₁₀ aryl-C₁₋₆-alkyl; or R¹¹ and R¹², together with theatom they are attached to, form a 4-7 membered ring; each R¹³ andR^(13a) is independently H, deuterium, C₁₋₆ alkyl, C₂₋₆ heteroalkyl,C₃₋₁₀ cycloalkyl, C₂₋₁₀ heterocyclyl, C₆₋₁₀ aryl, C₁₋₉ heteroaryl orC₆₋₁₀ aryl-C₁₋₆-alkyl; with the proviso that where R¹³ and R^(13a) arebonded to the same nitrogen atom, R¹³ and R^(13a), together with thenitrogen atom they are attached to, optionally form a substituted orunsubstituted 3-8 membered ring, spiro bicyclic ring or fused bicyclicring; each t is independently 0, 1, 2, 3 or 4; and each k isindependently 0, 1 or 2; or wherein each R⁹, R^(9a), R¹⁰ and R¹¹ isindependently H, deuterium, methyl, ethyl, isopropyl, cyclohexyl,isobutyl or phenyl; each R¹² is independently —C(═O)R¹³, —C(═O)—O—R¹³,—C(═O)NR¹³R^(13a), methyl, ethyl, propyl, phenyl, cyclohexyl,morpholinyl or piperidinyl; or R¹¹ and R¹², together with the atom theyare attached to, form a 4-7 membered ring; and each R¹³ and R^(13a) isindependently H, deuterium, methyl, ethyl, propyl, phenyl, cyclohexyl,morpholinyl or piperidinyl.
 45. (canceled)
 46. The compound according toclaim 11 having formula (VI):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl; wherein each ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀aryl, C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl and C₃₋₈ cycloalkyl-C₁₋₆-alkyl is optionallysubstituted with one or more substituents independently selected fromdeuterium, F, Cl, Br, hydroxy or cyano.
 47. The compound according toclaim 46 having formula (VII):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₃hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl, allyl,propargyl, trifluoroethyl, phenyl, pyranyl, morpholinyl, benzyl,piperazinyl, cyclopentyl, cyclopropyl, cyclohexyl or C₁₋₉ heteroaryl;wherein each of C₁₋₃ hydroxyalkyl, methyl, ethyl, isopropyl, isobutyl,tert-butyl, allyl, propargyl, trifluoroethyl, phenyl, pyranyl,morpholinyl, benzyl, piperazinyl, cyclopentyl, cyclopropyl, cyclohexyland C₁₋₉ heteroaryl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano.
 48. The compound according to claim 1 having formula (VIII) orformula (IX):

wherein each of R¹⁴ and R^(14a) is independently H, deuterium, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl,C₁₋₉ heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀aryl-C₁₋₆-alkyl, C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀heterocyclyl-C₁₋₆-alkyl or C₃₋₈ cycloalkyl-C₁₋₆-alkyl; each n₁ and n₂ isindependently 1, 2, 3 or 4; and wherein each of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl, C₂₋₆ heteroalkyl, C₆₋₁₀ aryl, C₁₋₉heteroaryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl-C₁₋₆-alkyl,C₁₋₉ heteroaryl-C₁₋₆-alkyl, C₂₋₁₀ heterocyclyl-C₁₋₆-alkyl and C₃₋₈cycloalkyl-C₁₋₆-alkyl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano.
 49. (canceled)
 50. The compound according to claim 1 havingformula (X):

wherein R^(5a) is H, deuterium, methyl, ethyl, F, Cl, Br or I; each ofR¹⁴ and R^(14a) is independently methyl, ethyl, phenyl, cyclohexyl,1-methyl propyl, isopropyl or tert-butyl; each of R¹⁶ and R^(16a) isindependently hydroxy, methoxy, ethoxy, phenoxy,

or tert-butoxy; wherein each of methyl, ethyl, phenyl, cyclohexyl,1-methyl propyl, isopropyl, methoxy, ethoxy, benzyl, tert-butoxy andtert-butyl is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano;wherein

wherein Bn is benzyl; A is

A′ is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:


51. The compound according to claim 1 having formula (XI):

wherein, each R^(5a) is independently H, deuterium, C₁₋₄ alkyl, F, Cl,Br or I; i is 1, 2, 3 or 4; each of Q¹ and Q² is independently NR⁶, O,S, C(═O) or (CR⁷R^(7a))_(e); each of e and f is independently 0, 1, 2, 3or 4; Q⁴ is —C(═O)—, —S(═O)— or —S(═O)₂; X¹ is O, NR⁶ or CR⁷R^(7a); eachof Y¹ and Y² is independently N or CR⁷; each R⁶, R⁷ and R^(7a) isindependently H, deuterium, C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclylor C₃₋₈ cycloalkyl; each of R¹⁴ and R^(14a) is independently H,deuterium, C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl or C₃₋₈cycloalkyl; each of R¹⁶ and R^(16a) is independently hydroxy, C₁₋₄alkoxy, C₆₋₁₀ aryloxy, C₂₋₁₀ heterocyclyl or C₃₋₈ cycloalkyl; whereineach of C₁₋₄ alkyl, C₆₋₁₀ aryl, C₂₋₁₀ heterocyclyl, C₃₋₈ cycloalkyl andC₆₋₁₀ aryloxy is optionally substituted with one or more substituentsindependently selected from deuterium, F, Cl, Br, hydroxy or cyano; A is

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:

each R^(5a) is independently H, deuterium, methyl, ethyl, F, Cl, Br orI; each R⁷ is independently H, deuterium, methyl, ethyl, isopropyl,phenyl or cyclohexyl; each of R¹⁴ and R^(14a) is independently methyl,ethyl, phenyl, cyclohexyl, 1-methyl propyl, isopropyl, isobutyl ortert-butyl; each of R¹⁶ and R^(16a) is independently hydroxy, methoxy,ethoxy, phenoxy,

or tert-butoxy; wherein each of methyl, ethyl, phenyl, cyclohexyl,1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy,tert-butoxy and tert-butyl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano.
 52. (canceled)
 53. The compound according to claim 1 havingformula (X′):

wherein R^(5a) is independently H, deuterium, methyl, ethyl, F, Cl, Bror I; each of Q¹ and Q² is independently CH₂, C(═O), CF₂, O, NR⁶ or S;X⁶ is O, S, NH or CH₂; R⁶ is H, deuterium, methyl, ethyl, isopropyl,phenyl or cyclohexyl; each of R¹⁴ and R^(14a) is independently methyl,ethyl, phenyl, cyclohexyl, 1-methyl propyl, isobutyl, isopropyl ortert-butyl; each of R¹⁶ and R^(16a) is independently hydroxy, methoxy,ethoxy, phenoxy,

or tert-butoxy; wherein each of methyl, ethyl, phenyl, cyclohexyl,1-methyl propyl, isopropyl, isobutyl, methoxy, ethoxy, phenoxy,tert-butoxy and tert-butyl is optionally substituted with one or moresubstituents independently selected from deuterium, F, Cl, Br, hydroxyor cyano; A is

A′ is

wherein

wherein R¹, R² and N—CH together form one of the following divalentgroups:

wherein R³, R⁴ and N—CH together form one of the following divalentgroups:


54. The compound of claim 1 having one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, ahydrate, a solvate, or a pharmaceutically acceptable salt thereof.
 55. Apharmaceutical composition comprising the compound according to claim 1;a pharmaceutically acceptable carrier, excipient, diluent, adjuvant,vehicle or a combination thereof; an anti-HCV agent; and at least oneHCV inhibitor; where the anti-HCV agent is an interferon, ribavirin,IL-2, IL-6, IL-12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, imiquimod, aninosine-5′-monophosphate dehydrogenase inhibitor, amantadine,rimantadine, bavituximab, human hepatitis C immune globulin (CIVACIR™),boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir,vaniprevir, faldaprevir, ABT-450, danoprevir, sovaprevir, MK-5172,vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ABT-267, EDP239,PPI-668, GS-5816, samatasvir (IDX-719), MK-8742, MK-8325, GSK-2336805,PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, ACH-1625,ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136,IDX-316, EP-013420, VBY-376, TMC-649128, R-7128, PSI-7977, INX-189,IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796,HCV-371, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072,PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, G1-59728, GL-60667,AZD-2795, TMC647055 or a combination thereof; wherein the interferon isinterferon α-2b, pegylated interferon α, interferon α-2a, pegylatedinterferon α-2a, consensus interferon-α, interferon γ or a combinationthereof; and wherein the at least one HCV inhibitor inhibits at leastone of HCV replication process and HCV viral protein function, whereinthe HCV replication process is a whole viral cycle consisting of HCVentry, uncoating, translation, replication, assembly and egress; andwherein the HCV viral protein is metalloproteinase, NS2, NS3, NS4A,NS4B, NS5A or NS5B; or an internal ribosome entry site (IRES) andinosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication. 56-62. (canceled)
 63. A method of inhibiting at least oneof HCV replication process and HCV viral protein function with thecompound according to claim 1, wherein the HCV replication process is awhole viral cycle consisting of HCV entry, uncoating, translation,replication, assembly and egress; and wherein the HCV viral protein ismetalloproteinase, NS2, NS3, NS4A, NS4B, NS5A or NS5B; or an internalribosome entry site (IRES) and inosine-5′-monophosphate dehydrogenase(IMPDH) required in HCV viral replication.
 64. A method of preventing,managing, treating or lessening the severity of HCV infection or a HCVdisorder in a patient comprising administering to the patient in need ofsuch treatment a therapeutically effective amount of the compoundaccording to claim
 1. 65-66. (canceled)
 67. A method of inhibiting atleast one of HCV replication process and HCV viral protein function withthe pharmaceutical composition according to claim 55, wherein the HCVreplication process is a whole viral cycle consisting of HCV entry,uncoating, translation, replication, assembly and egress; and whereinthe HCV viral protein is metalloproteinase, NS2, NS3, NS4A, NS4B, NS5Aor NS5B; or an internal ribosome entry site (IRES) andinosine-5′-monophosphate dehydrogenase (IMPDH) required in HCV viralreplication.
 68. A method of preventing, managing, treating or lesseningthe severity of HCV infection or a HCV disorder in a patient comprisingadministering to the patient in need of such treatment a therapeuticallyeffective amount of the pharmaceutical composition according to claim55.